Abstract
Gliomas are the most common brain tumors characterized by complicated heterogeneity. The genetic, molecular, and histological pathology of gliomas is characterized by high neuro-inflammation. The inflammatory microenvironment in the central nervous system (CNS) has been closely linked with inflammasomes that control the inflammatory response and coordinate innate host defenses. Dysregulation of the inflammasome causes an abnormal inflammatory response, leading to carcinogenesis in glioma. Because of the clinical importance of the various physiological properties of the inflammasome in glioma, the inflammasome has been suggested as a promising treatment target for glioma management. Here, we summarize the current knowledge on the contribution of the inflammasomes in glioma and therapeutic insights.
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Introduction
Glioma is the most prevalent intracranial brain tumor (comprising 81% of malignant brain tumors) that is thought to be driven by neuroglial or progenitor cells [1]. Although optimal standard treatments based on the biological or clinical background of glioma have been developed, the prognosis has not drastically improved due to the complicated heterogeneity and aggressive microenvironment of the glioma [2]. Stagnant survival statistics and increased malignancy demonstrate the urgent need for continued research to develop more effective therapies for glioma [1].
The tumor microenvironment (TME) created by interactions between malignant and non-transformed cells acts as a host supporting the expansion and invasion of tumors, promoting neoplastic transformation, protecting the tumor from host immunity, and providing niches for dormant metastases to flourish [3, 4]. Among the highly heterogeneous elements of the TME, an aggressive inflammatory process is one of the vital elements leading to dismal treatment results of glioma and glioblastoma [5]. Malignant progression of glioma relates to a neuroinflammatory response, deemed as a hallmark of tumor growth, invasion, angiogenesis, and metastasis [6]. A neuroinflammation-enriched TME developed through the production of pro-inflammatory cytokines, chemokines, and growth factors facilitates an immune-suppressive response and aids in the survival capacity of glioma cells [7, 8]. The clinical significance of treatment of chronic inflammation in the central nervous system (CNS) shows therapeutic potential for gliomas at the molecular level [9].
The association between neuroinflammation and the inflammasome (multiprotein complex) involved in the innate immune system is an emerging research topic in glioma [10, 11]. Mounting evidence for an inflammasome-mediated inflammatory response describes the erroneous functions of the innate immune system in glioma TME [12]. Generation of proinflammatory cytokine by inflammasome activation can promote glioma progression [12]. Because the inflammasome has clear biological implications in glioma, clinical studies on its identity are essential. In this review, we discuss the latest insights into the function and molecular mechanism of inflammasomes in glioma, suggesting a therapeutic approach on a molecular level.
Pathology of glioma
The common symptoms of glioma include seizure, cognitive disorder, aphasia, motor paresis, and headache [13]. Physical diagnosis of patients with glioma, including those with glioblastoma, the most aggressive form of glioma, is based on detecting the pathological origin and specific subtype of cancer via neurosurgical procedures and molecular and histological examinations [14]. Based on the diagnosis using computed tomography or magnetic resonance imaging assessments, treatment decisions involving surgical resection, radiotherapy, and TMZ chemotherapy are suitably established [14]. In 2021, the fifth edition of the World Health Organization (WHO) classification of CNS was published, which contains general changes, including the taxonomy and nomenclature of glioma [15]. The novel stratification of glioma with 1p/19q co-deletion based on fluorescence in situ hybridization (FISH) analysis and IDH mutant or wildtype based on IHC analysis became more sophisticated with additional diagnostic evaluation indices such as loss of ATRX expression or TERT promoter mutations, the presence of TP53 or histone H3 mutations, EGFR amplification, and CDKN2A/B alterations [16]. Based on the newly developed criteria, numerous biological classifications and treatment strategies are being proposed [15, 16]. These advances have resulted in an improved understanding of the molecular pathogenesis of glioma with somatic mutations, hyperinflammatory responses, metabolic dysfunction, immunoediting, and cell plasticity.
Large-scale efforts have been made to identify the major genetic and epigenetic alterations in glioma [17]. The data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) project has aided in understanding the molecular landscape of glioma, allowing the establishment of several subtypes and genomic characteristics [18, 19]. In line with previous reports, the status in IDH1/2, 1p/19q, TP53, CIC, PTEN, EGFR, MGMT, TERT, ATRX, and Ras/MAPK and extrachromosomal DNA were used as pathological indications of glioma [20,21,22]. These approaches further subdivided the glioma molecular subtypes into neural, proneural, classical, and mesenchymal types [15, 23].
Until recently, histological examination was one of the “gold standards” for diagnosing glioma [24]. Gliomas are generally graded using WHO grades 1–4 based on malignancy signatures, including the degree of mitotic activity, atypia, microvascular proliferation, pseudopalisading necrosis, and specific hallmarks [15]. Although this histological classification has developed over the years, it has some limitations, such as interobserver variability and apprehensive subject quality during in vitro examinations [25]. Thus, to improve our understanding of histological information, molecular features and clinical opinions should be considered together [26].
For several decades, the cellular origin of glioma has been a hot topic of interest in tumorigenesis in the CNS [27]. Numerous scholars postulate that gliomas originate from neural stem cell (NSC) lineages such as neurons, oligodendrocyte precursor cells (OPCs), oligodendrocytes, and astrocytes [27, 28]. OPCs expressing NG2, OLIG2, A2B5, and PDGFRα are the most abundant cells in CNS, and the proliferation of adult OPCs may play a pathological role in glioma development via responses to bFGF and PDGF-AA [29,30,31]. Astrocytes were identified as the causative cells of gliomas in the 1980s [32], and features such as mutated epidermal growth factor receptor (EGFR) and activation of H-RAS, considered representative signatures of gliomas, were revealed in a mouse model [33,34,35]. It has been verified in animal models that other cells, such as glial restricted progenitor cell (GRPC) and astrocyte precursor cell (APC), are cells of glioma origin [36].
The TME throws the physiological phenotype into disorder by closely interacting with diverse elements [37]. This is no different in glioma; in fact, the TME in glioma has a complex heterogeneity that is difficult to understand [38, 39]. Large-scale studies conducted to understand the TME and reduce interindividual variability have provided a fragmented genetic status of cells [40, 41]. Aggressive genetic and phenotypic profiles of glioma with proliferative, invasive, and immune-suppressive signatures contribute to the formation of a malignant signaling axis via the acceleration of an autocrine or paracrine loop [42,43,44]. These common features of gliomas represent a fundamental baseline for standard treatment and follow-up management [45, 46]. In recent years, single-cell RNA sequencing (scRNA-seq) has allowed the study of the biological properties of individuals with unprecedented resolution [47,48,49]. Single-cell landscapes, supplemented with bulk RNA-seq and histological staining results, have provided insights into the TME, including details regarding the functions of specific cells and molecules [47, 50]. To date, the progress has closely revealed pathological characteristics of specific molecular subtypes, cell types, and molecules within gliomas [15, 51]. In particular, the mesenchymal signature of glioma (also called mesenchymal subtype) exhibits a high inflammatory response, potential cellular plasticity, BBB instability, and immune infiltration, and myeloid lineage cells, including microglia and macrophages, may play a role in increasing the malignancy of the tumor microenvironment [52,53,54]. In addition, positionally resolved multi-omics with spatial transcriptomic analysis may help decipher the tumoral development process and bidirectional cell-to-cell interdependence in the TME of gliomas [55, 56]. Dissecting the composition and functional heterogeneity of the TME of tumor cells and infiltrating cells would extend our understanding of glioma and allow us to improve the therapeutic efficacy for good prognosis of patients.
Neuroinflammation in glioma
Classically, the CNS was supposed to be an “immune privileged” site following the rejection of transferred foreign tissue into the brain [57]. This is due to a specialized microenvironment including the BBB, inner blood-retinal barrier, low MHC expression, draining lymphatic insufficiency, specialized antigen-presenting cells, and plentiful anti-inflammatory modulators to protect normal neurons from aggressive immune responses [58, 59]. Although the characteristics of the natural status of the CNS are necessary for the maintenance of the environmental composition and proper function, these can be fatal in CNS diseases [60]. Importantly, studies for CNS disease, including glioma have focused on the pathogenic alteration of inflammatory response in the TME [61].
Neuroinflammation is closely linked to the vascular barrier. BBB is a selectively permeable barrier secured by endothelial cells linked to each other by tight junctions, a pericyte-embedded layer, and an astrocyte end-feet anchor [60, 62]. In the glioma, endogenous or exogenous pathogenic stimuli cause devastating neuroinflammation, altering the BBB cell layer characteristics and permeability of blood vessels [10, 63, 64]. A compromised BBB by an enhanced inflammatory response is influenced by diverse elements, including TNF-α, IL-1β, TGF-β, HIF-1α, VEGF, and metalloproteinase induced by inflamed immune cells [65,66,67]. Although BBB breakdown by neuroinflammation supports the progression of glioma in an autocrine and paracrine manner, with respect to immunotherapy, it is paradoxically that it allows for easy infiltration of peripheral immune cells to the CNS [68, 69].
Inflammatory response mediators form an important checkpoint in glioma. At the cellular level, myeloid cells (~ 60% of immune cells in glioma) are the most common immune cell type in glioma [10]. Representatively, proliferative and pro-inflammatory microglial cells (called brain resident myeloid cells) have a significantly positive correlation with glioblastoma progression [70]. Interestingly, microglia and macrophages can be polarized into two different phenotypes (M1: pro-inflammatory role, M2 type: anti-inflammatory role), and the M1/M2 ratio significantly affects the neuroinflammatory microenvironment [71]. These cells release inflammatory cytokines and chemokines such as IL-1β, TNF-α, IL-6, IL-12, IL-23, CCL2, CCL3, CCL4, CCL5, CXCL10, and CCL12, causing neuroinflammatory disorders [72]. Furthermore, glioma-associated microglia/macrophages (GAMs), which account for approximately 30% of the surgically resected glioma mass, play a key role in neuroinflammation [10]. GAMs not only produce immunosuppressive cytokines and tumor growth factors favorable for tumor growth but promote glioma progression by indiscriminate induction of inflammatory cytokines [73, 74]. In this regard, therapeutic strategies targeting specific molecules expressed primarily in these cells have been described considerably [75]. In contrast, a chronic inflammatory response in glioma and glioblastoma promotes the accumulation and activation of MDSCs, which inhibits anti-tumor immunity [76]. These cells are recruited by SDF-1, CCL2, and CXCL2 and then proliferate in response to IL-6, VEGF, GM-CSF, and PGE2 released by the glioma cells, further compromising the inflammatory microenvironment [77,78,79]. Astrocytes, known to be the most closely related to neuroinflammation among cells not of the myeloid lineage, originally orchestrate neuronal development by secreting synaptogenic molecules and pruning excess synapses [80,81,82]. Among diverse astrocyte populations, reactive astrocytes (upregulated GFAP astrocyte) exhibit neurotoxic activity in various neurodegenerative diseases and promote inflammatory signaling pathways, including JAK/STAT3, calcineurin, NF-κB, and MAPK pathways [83, 84]. Taken together, the pathological processes of these cells, mediating an inflammatory response or induced by inflammation, may enhance the proliferation, invasion, chemoresistance, and immune protection of tumor cells in glioma.
To completely understand the process of neuroinflammation in glioma, the molecular network must be approached as a means of understanding cell-to-cell communication [85]. The functional and phenotypic landscapes of the cytokines, chemokines, growth factors, cis or trans elements, and cytosolic nucleic acids involved in the inflammatory microenvironment have already been specifically described for CNS diseases [85]. These molecules are not limited to the inflammatory response but show associations with various mechanisms such as metabolism, homeostasis, DNA repair, cell plasticity, and immunomodulation and form intra- or inter-links with these [86]. Therefore, discovery and validation of novel mechanisms in glioma, as well as identification of collaboration between them, will provide the foundation for a complete understanding of the inflammatory microenvironment in gliomas (Fig. 1).
Association of the inflammasome with glioma
Inflammasomes are intracellular multimeric protein complexes comprising a NOD-like receptor (NLR), adaptor apoptosis-associated speck-like protein (ASC), and pro-caspase-1, which were discovered in 2002 [87]. They elicit the innate immune response via caspase-1 cleavage and secretion of pro-inflammatory cytokines such as IL-1β and IL-18 against pathogenic microorganisms or danger signals [88]. Based on the general background of the inflammasome in various diseases, reports of associations with glioma have been analyzed, and we have discussed the advances in the overall view of the inflammasome in glioma (Fig. 2).
As with other tumors or autoimmune diseases, various inflammasomes, including NLRP3 and NLRC4, have been reported in glioma. Although attention has been paid to the differences in the composition and function of inflammasomes due to the spatial specificity of the CNS bearing the BBB, the inflammasomes are highly conserved across tissues and cell types [12]. Assembly and activation of the inflammasome is a key function mediated by the innate immune response, and recent advances have significantly contributed to understanding the macromolecular identity of the inflammasome in glioma [12]. Representative upstream signals that induce the inflammasome are known to be pattern recognition receptors (PRRs) such as the Toll-like receptor (TLR) and RIG-I-like receptor (RLR) families [89, 90]. Current reports have suggested the contribution of the PRRs acting in a paracrine fashion to the development and malignancy of glioma [91,92,93,94]. In particular, the TLR families, including TLR1, TLR2, TLR3, TLR4, TLR6, and TLR9, are highly expressed in the TME of glioma, both in vitro and in vivo, leading to neuroinflammation [93, 95,96,97,98,99,100]. Mounting expression of TLRs in numerous cell types of glioma TME such as microglia, plasmacytoid DCs (pDCs), glioma stem cell (GSCs), GAMs, and astrocytes accelerates the network of signaling events that result in de novo synthesis via transcriptional modulation or non-proteinaceous signaling molecules [96, 101,102,103,104,105,106,107]. Upon PRR sensing of certain stimuli, the NF-κB signaling pathway is activated, which further induces NLR protein (known as inflammasome receptor protein) transcription, pro-IL-1β and pro-IL-18 transcription, and the inflammatory response both locally and systemically through a positive feedback loop [101]. Importantly, these steps are defined as the priming step (also called the first step of inflammasome assembly and activation), which allows the maintenance of constitutively high levels of pro-inflammatory cytokines and inflammasome sub-molecules. The NF-κB pathway, a key element of the priming step of the inflammasome, plays a pathological role in gliomas [108]. Meanwhile, the recognition of PAMPs or danger signals by a unique PRR results in proper assembly and activation of inflammasomes (second step of inflammasome activation) [109]. Although there are fundamental differences between inflammasomes that depend on stimuli, generally, canonical inflammasomes serve as a scaffold to recruit adaptor proteins known as ASCs, which consist of two death-fold domains, a pyrin domain (PYD) and a caspase recruitment domain (CARD), and inactive zymogen pro-caspase-1 [110]. Subsequent oligomerization of pro-caspase-1 induces their autoproteolytic cleavage into active caspase-1 [111]. Activated caspase-1 is a cysteine-dependent protease that cleaves the precursor cytokines pro-IL-1β and pro-IL-18, generating the active forms of IL-1β and IL-18, respectively [111]. At present, the intermediate and final products formed during inflammasome assembly and activation have been identified as important growth- and motility-driving elements in gliomas [112, 113]. Although the mechanisms underlying the glioma inflammasome activation remain unclear, the recruitment and activation of the component molecules of the inflammasomes are associated with malignancy in gliomas [12]. For example, berberine treatment inhibits glioma growth by inactivating caspase-1-mediated inflammatory cytokines via ERK1/2 regulation [114]. In this regard, the pharmacological inhibition of the inflammasome receptor protein, adaptor protein, caspase-1, and pro-inflammatory cytokines may facilitate glioma management.
To date, numerous receptor proteins of inflammasome assembly have been identified, including NLRP1, NLRP2, NLRP3, NLRC4, NLRP6, NLRP12, AIM2, IFI16, and pyrin [110]. As described above, these proteins recruit adapter proteins and inactive caspase-1 to assemble an inflammasome platform. Importantly, two pathways called canonical and non-canonical pathways are involved in the subsequent inflammasome activation process [111]. Recent developments toward our understanding of the canonical pathway (the inflammasome-caspase-1-proinflammatory cytokine axis) of inflammasome activation in glioma have been expertly reviewed in depth [111]. However, the role of the non-canonical inflammasome pathway in glioma is still unclear. In general, the non-canonical inflammasome pathway, which targets caspase-11 (in mice), caspase-4 (in human) and caspase-5 (in human), can restore the activation of the canonical inflammasome pathway [115]. Direct sensing of LPS and gram-negative bacteria by caspase-4 or caspase-5 induces cleavage and oligomerization of caspase-4 or caspase-5 [115]. These active forms directly promote pyroptosis, called pro-inflammatory cell death, via cleavage of the pore-forming protein gasdermin D (GSDMD) [115]. The non-canonical inflammasome pathway, similar to the canonical inflammasome pathway, is intertwined with pathological functions in CNS diseases [116, 117]. However, the overall mechanism of action of the non-canonical inflammasomes in glioma has not been presented, but the functions of the individual molecules associated with them have been investigated. In fact, 15 differentially expressed genes, including caspase-5, were upregulated in glioma tissues (n = 667) compared with those in normal brain tissues (n = 1152), suggesting a prognostic value for the pyroptosis-related gene signature in glioma [118]. Cox regression, Kaplan–Meier analysis, and IHC results showed that GSDMD might be a novel biomarker for the prognosis and TMZ sensitivity in glioma [119]. There is additional evidence from a computational analysis that GSDMD is significantly positively correlated with glioma malignancies [120].
Role of inflammasomes in glioma
NLRP3 inflammasome
Among the inflammasomes, the NLRP3 inflammasome is the most analyzed protein complex [121]. Generally, NLRP3 is induced by a signal through stimulation of TLRs, NLRs, and cytokine receptors in the myeloid cell lineage, which undergo a priming step (which is an initiation activation) and are subsequently activated by NLRP3 stimulators, including extracellular pathogens, ATP, RNA–DNA hybrids, ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS), and lysosomal damage, to mediate the innate immune response [121]. Since 2014, the function of the NLRP3 inflammasome in gliomas has been closely investigated. Aggressive expression and activity of the NLRP3 inflammasome were observed in cells derived from glioma patients [113], suggesting that the NLRP3 inflammasome is a potential marker of glioma progression [113, 122]. Ever since the pathological function of NLRP3 in glioma was understood, its regulatory mechanisms and potential as a therapeutic target have been evaluated. Emerging evidence regarding the regulatory mechanism of the NLRP3 inflammasome has shown that NLRP3 can induce the EMT and PTEN/AKT signaling pathways and lead to glioma cell proliferation, apoptosis, and metastasis [123]. Alendronate (ALD: one of the nitrogen-containing bisphosphonates) treatment of glioma cell line causes augmented NLRP3 inflammasome activity, apoptosis, and mitochondrial damage, indicating that ALD is associated with impairment of the mevalonate pathway, which inhibits cholesterol synthesis and protein prenylation [124]. Another report has exhibited that the NLRP3 inflammasome induces proliferation and invasion of glioma cells via regulation of IL-1β and NF-κB p65 signaling [125]. Importantly, a report on the upstream signaling pathway of the NLRP3 inflammasome in gliomas has been published, and activation of the ERK-dependent NF-κB has been shown to activate the NLRP3 inflammasome mediated by vimentin in EV-71-infected glioma [126]. Considering these findings, the outline of the potential axis of the NLRP3 inflammasome involved in the induction and regulation of gliomas has been revealed.
In addition to the previous work, studies to build basic knowledge on NLRP3 inflammasome-targeted therapeutic approaches in gliomas have been performed in parallel. Beta-hydroxybutyrate (BHB) inhibits the migration of glioma by suppressing NLRP3 inflammasome expression and activation [127]. WP1066, which inhibits the activation of STAT3 by directly targeting JAKs, also suppresses glioma cells via NLRP3 inflammasome inhibition independently of STAT3 inhibition [128]. Additional evidence suggests that NLRP3 inflammasome blockade therapy using IP-Se-06 (selenylated imidazo[1,2-a]pyridine) induces anti-proliferation of glioma cells via inhibition of p38 MAPK and p-p38, leading to inhibition of the NLRP3 inflammasome [129]. In addition, in-depth glioma studies were conducted on the effects and mechanisms of the NLRP3 inflammasome in terms of cellular plasticity including M1 macrophage polarization and drug resistance [130, 131]. The simultaneous physiological, etiological, and therapeutic approaches targeting the NLRP3 inflammasome in glioma have led to remarkable progress, and efforts are being made to fully understand the role of the NLRP3 inflammasome through a translational study based on previous studies.
NLRC4 inflammasome
The origins of NLRC4 inflammasome have been explored earlier along with that of NLRP3. Various approaches to investigate its structure and function have been attempted [132,133,134,135]. In general, the NLRC4 inflammasome is involved in innate immunity against pathogens such as bacterial flagellin and T3SS needle and rod protein [135]. While it is closely modulated by transcriptional regulation, post-translational modification (PTM), specific phosphorylation, and ubiquitination, it promotes the pathogenesis of various autoimmune diseases and tumors due to its abnormally high expression and dysregulation [136,137,138].
The role of the NLRC4 inflammasome in gliomas was first described in 2019, and our findings identified that robust expression and activation of NLRC4 are associated with glioma progression and prognosis [139]. Expression profiles of inflammasomes in glioma support the involvement of NLRC4 in gliomas, and based on this, more specific functional studies have been subsequently conducted [140]. Recently, progress has been made in studying the function and molecular association of the NLRC4 inflammasome in glioma. The NLRC4 expression shows a significantly positive correlation with Tim-3 and Gal-9 expression. The Tim3-Gal-9 axis upregulates the expression and activation of the NLRC4 inflammasome to induce an inflammatory response in glioma [141]. Notably, inflammasomes are generally expressed in myeloid lineage cells, whereas NLRC4 inflammasome expression is observed in astrocytes and microglia of glioma, suggesting that astrocytes might mediate neuroinflammatory responses [139, 141]. The nature of the NLRC4 inflammasomes in glioma remains unclear. They remain functionally controversial and are associated with the NLRP3 inflammasome in other diseases [142,143,144]. Hence, NLRC4 should not only be investigated closely in glioma but also for additional molecular links and mechanisms, including non-canonical pathways and molecular signaling pathways.
NLRP6 inflammasome
NLRP6, which shows robust expression in gliomas, also belongs to the NLR family, similar to NLRP3 and NLRC4 [145]. Fewer reports of NLRP6 in glioma have been made compared to NLRP3 and NLRC4, but some progress has been made in recent years. In 2019, a clear structure of NLRP6 was elucidated using cryo-electron microscopy (cryo-EM) and crystallography, and the molecular mechanism underlying the assembly and activation of NLRP6 was elucidated, along with functional studies being undertaken in gliomas [146]. In terms of the function of the NLRP6 inflammasome, its function and associated molecules were slightly different depending on the organ in which it is expressed [147]. Importantly, the functions of the NLRP6 inflammasome in gliomas lead to a rather aggressive acceleration of carcinogenesis. NLRP6 transcriptionally induced by SP1 affects the subsequent increase in NLRP6 inflammasome activation and further causes immune escape from CD8+ T cells and radiation resistance of glioma cells [148]. In addition, the malignancy of gliomas has a positive correlation with the inflammatory response [61], and a significant decrease in the inflammatory response via the inhibition of NLRP6 through miR-331-3p was observed in microglial cell lines [149].
NLRP6 expression is normally regulated by upstream microbial and metabolic stimuli [150]. Recently, peroxisome proliferator-activated receptor γ (PPAR-γ) and its agonist rosiglitazone (as known to be metabolic regulator) came to be known as a representative positive regulator of NLRP6 expression [151, 152]. These regulators exhibited amplified expression in a mesenchymal subtype known to have a poor prognosis among glioblastomas (grade 4 glioma) and were suggested to be potential therapeutic target molecules [153]. So far, the roles of NLRP6 in glioma have been unveiled, and a rough outline of its overall landscape has been obtained; however, numerous aspects remain to be solved, such as the role in specific major cell types and exosomes, including the regulatory signaling pathway.
NLRP12 inflammasome
The first description of NLRP12 involved its contribution to inflammasome activation in response to Yersinia Pestis infection, which Vladimer revealed in 2012 [154]. This finding promoted the functional studies of NLRP12 that led to determining its function as an innate immune sensor and its role in other conditions, including bacterial infection, autoimmune diseases, and tumors [155,156,157]. Whether NLRP12 is an inhibitor or inducer of the inflammatory response is still controversial [158]. In glioma, the NLRP12 inflammasome is highly expressed. Differential expression profile analysis has shown its potential as a prognostic marker in glioblastoma [159]. Furthermore, inhibition of NLRP12 using siRNA in glioblastoma cell lines inhibited cell proliferation [159]. In contrast, in another study, NLRP12 was strongly activated in a glioma cell line in which the SSFA2 gene was silenced. The genes strongly related to NLRP12 were found through subsequent ingenuity pathway analysis (IPA) based on microarray data [160]. Thus, pro-inflammatory molecules and cell cycle molecules showed a positive correlation with NLRP12, but IL-2 cytokines showed a very strong negative correlation [160]. Based on the above findings, although the function of NLRP12 as an innate immune sensor or an anti-inflammatory protein under various conditions is conflicting, direct or indirect evidence for its tumor-friendly characteristics in gliomas has been observed [161]. To fully understand the role of the NLPR12 inflammasome in glioma, the regulatory mechanism and additional functions must be investigated using various in vivo models.
AIM2 inflammasome
Absent in melanoma 2 (AIM2), a pyrin and HIN domain-containing (PYHIN) family member, is a representative inflammasome receptor protein that recognizes aberrant cytoplasmic double-strand DNA (dsDNA) [162, 163]. In the presence of a stimulus, AIM2 recruits the adaptor protein called ASC via interactions between PYDs [164,165,166]. This assembly induces the activity of caspase-1 and induces apoptosis as well as maturation and secretion of inflammatory cytokines, leading to innate immune responses against dsDNA of bacterial, viral, parasitic, and self-origins [164, 167,168,169,170]. Although there have been considerable studies on the pathological function and mechanism of the AIM2 inflammasome in other tumors, reports in gliomas have been relatively unclear [171]. Some functional advances have been made from the viewpoint of CNS that the AIM2 inflammasome induced by macrophages or endothelial cells in the brain pathologically leads to brain injury and chronic post-stroke cognitive impairment [172]. Notably, since 2019, the existence and function of the AIM2 inflammasome in glioma has been elucidated. AIM2 is extensively expressed in G2, G3, and G4 gliomas in TCGA database, networks with each inflammasome receptor, and epigenetic alteration patterns [140]. From functional aspects, inhibition of the AIM2 inflammasome increases the proliferation of gliomas and increases temozolomide resistance in vitro, a somewhat controversial function compared to its function in other diseases [173]. Another controversial function of AIM2 inflammasome in glioma was hinted at in the late phase of experimental autoimmune encephalomyelitis (EAE) and a mouse model of multiple sclerosis [174]. Indeed, activation of the AIM2 inflammasome in astrocytes during EAE did not alter the gene expression of apoptosis components and pro-inflammatory cytokines, suggesting distinct functional aspects for AIM2 in the CNS [174]. Meanwhile, alterations in the AIM2 inflammasome during tumor treating fields (TTFields) therapy, a non-invasive regional anti-mitotic treatment modality with minimal systemic toxicity, for glioblastoma were reported in a recent study [175]. The TTFields therapy induces AIM2 formation and activation in GSCs, leading to membrane-damaged cell death of GSCs [175]. These advances help us understand the role of the AIM2 inflammasome and suggest a direction for further study; however, it is necessary to understand the function and molecular connection of the AIM2 inflammasome with glioma in more detail and evaluate its potential as a diagnostic, prognostic, and therapeutic target molecule.
Other inflammasomes and glioma
In addition to the previously mentioned inflammasomes, other inflammasome complexes in gliomas have been reported. The NLRP1 inflammasome is known to be positively associated with glioma in LGG and GBM, as demonstrated by in silico analysis. In terms of the function of the NLPR1 inflammasome in CNS disease, including glioma, the NLRP1 inflammasome in the hippocampus is positively correlated with neuroinflammation and neurofibrillary formation in Alzheimer’s disease (AD) [176]. Furthermore, NLRP1 expression could affect immune cell infiltration in glioma, as observed through TIMER database analysis [177]. Interestingly, in glioma or melanoma, TMZ-induced upregulation of NLRP1 and IL-1β is linked to the Notch1 signaling pathway and, subsequently, to the acquisition of drug resistance, as revealed by MAPK inhibitors [178,179,180,181,182]. Some studies have focused on the presence and function of NLRP2 and NLRP7 in other tumors, but their presence in glioma is rare [183, 184]. In 2022, mutation profiling of these genes, including pyroptosis-associated genes, revealed the significant co-occurrences of mutations in glioma [185]. In particular, the NLRP2 inflammasome is expressed upon the stimulation of the damage-associated molecular pattern (DAMP) ATP in human astrocytes and is expected to play a potential role in glioma as it induces pro-inflammatory cytokine activation through NLRP2 inflammasome activation by P2X7 receptor and pannexin 1 channel [186]. In addition, studies have focused on several inflammasomes, including hypomethylation of IFI16 in glioma [187]. Although biological structures and functions of inflammasomes have been conserved according to their various origins, the investigation of their identity in gliomas should be supplemented by further study.
Potential therapeutic strategies for inflammasomes in glioma
In a voluminous effort, promising therapeutic results in glioma have been shown in studies targeting inflammasome. Current research focuses on inhibiting inflammasome-associated proteins involved in the priming, assembly, and activation of the inflammasome. In this section, we discuss potential therapeutic strategies targeting the inflammasome-associated molecules involved in each step of assembly and activation in glioma.
Targeting the priming pathway of inflammasomes
The TLR family of proteins is the most upstream receptor for the priming, assembly, and activation of the canonical or non-canonical inflammasome pathways. Previous studies have reported that TLR4 is overexpressed in astrocytes, glioma cell lines, GBM tissues, and CD133+ cancer stem cells [188,189,190]. Inhibition of TLR4 signaling with shRNA induces chemotherapy-mediated apoptosis of glioma CD133+ cancer stem cells [191]. p65 nuclear translocation by non-canonical TLR4 signal/activation of DNA repair genes is positively correlated with the survival of U87MG glioma cells, suggesting that p65 is a potential therapeutic target for the inflammasome [192]. TLR2 also plays pathological roles in glioma, including immune evasion and the development and progression of glioma cells [99, 193]. Treatments targeting the expression or activation of TLR2 in GSCs within the glioma may be efficient strategies [107]. TRIF and MyD88, which are intracellular adaptor proteins of TLR, can also be targeted with inflammasome therapy in glioma, leading to the destruction of the TLR and NF-κB loop to sustain an inflammatory response [194]. Aberrant activation of NF-κB, a downstream transcription factor of the TLR pathway, is a hallmark of glioma [195]. Inhibition of these signaling pathways results in significant programmed death of glioma cells, and these inhibitors can be used as therapeutic adjuvants to the TMZ standard chemotherapy for glioma [196]. Inhibitors of TLR and NF-κB, the key molecules in the inflammasome priming step, have been described earlier, but their efficacy in gliomas and the mode of action in the inflammasome axis are still unclear [197, 198]. In addition, indirect inflammasome inhibition by targeting multiple elements that regulate the priming step, including ROS, hypoxia, metabolites, lipid metabolites, and complement proteins, although not well known in glioma, can be expected with novel therapeutic approaches [199]. For the clinical application of candidate drugs targeting these priming step-related molecules, additional in vitro and in vivo validations are essential.
Targeting the assembly and activation of the inflammasomes
A promising therapeutic strategy targeting receptor proteins that play an important role in assembling and activating inflammasomes was suggested earlier [200]. Representatively, numerous pharmacological inhibitors of the NLRP3 inflammasome have been described [201]. Indirect or direct inhibitors of NLRP3 involve Glyburide, JC124, FC11A-2, Parthenolide, VX765, BHB, MCC950, and Tranilast [201]. Although candidate agents targeting receptor proteins in gliomas are relatively unclear compared to such agents in other diseases, some assessments have been performed. BHB, WP1066, and IP-Se-06 were found to directly inhibit glioma migration, proliferation, and viability by inhibiting the expression or activity of the NLRP3 inflammasome in glioma [127,128,129]. Additionally, miR-331-3p, SP1 inhibitor, and PPAR-γ inhibitors can prevent the expression of NLRP6 in glioma [131, 148, 149]. Inhibition of P2X7 and pannexin 1 also reduces the inflammatory response of gliomas by inhibiting the expression of the NLRP2 inflammasome [186, 202].
In a recent study, inhibition of TIM-3, an immune checkpoint molecule robustly expressed in glioma, was suggested as a therapeutic strategy to inhibit the NLRC4 inflammasome in glioma cells [139, 203]. In fact, in silico and in vitro validation results regarding the Tim-3/Gal-9 axis and the NLRC4 inflammasome showed a significantly positive correlation according to the WHO glioma grade, and it was found that Tim-3 regulates the expression and activity of the NLRC4 inflammasome [141]. These results provide potential insights into the networks between various biological mechanisms and inflammasomes and implicate dual-acting therapeutic strategies involving target therapy for inflammasomes and other previously known mechanisms.
Notably, there is evidence suggesting that adaptor proteins of the inflammasome are potential therapeutic targets for glioma [204]. For example, PYCARD, known as apoptosis-associated speck-like protein containing a CARD (ASC), plays a role as an adaptor to bridge sensor proteins and effector molecules [88]. A CARD-associated risk score (CARS) was positively correlated with the poor prognosis of glioma patients who underwent standard therapy [205]. These advances using an inflammasome-associated gene set allow predicting the therapeutic potency in glioma patients.
The role of berberine, a potential therapeutic agent targeting caspase-1, an important hall marker of inflammasome activity, was investigated in a glioma cell line [114]. Berberine directly inhibits caspase-1 activation via the ERK1/2 signaling pathway in glioma cells, leading to inhibition of the expression of pro-inflammatory cytokines such as IL-1β and IL-18 [114]. Anakinra, a recombinant IL-1 receptor agonist, is a representative drug targeting aggressive inflammation [206]. Anakinra inhibited the expression of IL-1β in tumor cells and PBMCs of GBM, inhibited the proliferation and migration of tumor cells, and reduced inflammatory signals [207].
Therapeutic aspects for the non-canonical inflammasome pathway
Although fewer inhibitors of the non-canonical inflammasome-pathway-associated molecules have been identified compared with those for canonical inflammasome-pathway-associated molecules, they exhibit biological evidence as potential prognostic biomarkers [208]. The transcriptional level of GSDMD in gliomas increased according to the WHO grade, and it was verified as a prognostic marker through survival analysis, Cox-regression analysis, and histological staining [208]. Importantly, the expression pattern of GSDMD showed differences according to the status of IDH1/2 mutation and 1p19q co-deletion, indicating detailed molecular characteristics of gliomas and the biological link of the inflammasome [208]. Based on these advances, the potential characteristics of the inflammasome according to the molecular and histological subtype of glioma can serve as a promising therapeutic candidate target for personalized therapy. One limitation in the research on the non-canonical pathway is that caspase-4 and caspase-5, the key regulators of the non-canonical inflammasome, have not yet been explored in gliomas; thus, functional studies on these are urgently required. Collectively, we summarized the potential therapeutic candidates for target molecules in the inflammasome axis (Table 1).
Conclusions
The biological findings on how inflammasomes are activated in tumors have increased their clinical importance. Importantly, an understanding of the balance between beneficial and detrimental inflammasome in tumor cells is essential. In particular, inflammasome activity reinforces tumor progression and invasion in glioma. However, activation of not all inflammasome proteins can be considered harmful in glioma, and the therapeutic inhibition of this axis has to be balanced against its beneficial contribution.
Previous studies on the role of inflammasomes in glioma have provided fragmentary approaches and have not yet led to any clinical significance. However, further mechanistic insights into the role of the inflammasome in glioma will provide opportunities to develop therapies for patients with other inflammatory CNS diseases. In addition, clarification of the association between the inflammasome and its underlying mechanisms in glioma may indicate a new direction for glioma diagnosis, prognosis, and therapy.
Availability of data and materials
Not applicable.
Abbreviations
- AD:
-
Alzheimer’s Disease
- AIM2:
-
Absent in Melanoma 2
- ALD:
-
Alendronate
- APC:
-
Astrocyte Precursor Cell
- ASC:
-
Apoptosis-associated Speck-like protein containing a CARD
- ATRX:
-
Alpha-Thalassemia/Mental Retardation, X-linked
- BBB:
-
Blood–Brain Barrier
- bFGF:
-
Basic Fibroblast Growth Factor
- BHB:
-
Beta-Hydroxybutyrate
- BRB:
-
Blood-Retinal Barrier
- CCL12:
-
C–C Motif Chemokine Ligand 12
- CCL2:
-
C–C Motif Chemokine Ligand 2
- CCL3:
-
C–C Motif Chemokine Ligand 3
- CCL4:
-
C–C Motif Chemokine Ligand 4
- CCL5:
-
C–C Motif Chemokine Ligand 5
- CGGA:
-
Chinese Glioma Genome Atlas
- CIC:
-
Capicua Transcriptional Repressor
- CNS:
-
Central Nervous System
- cryo-EM:
-
Cryo-Electron Microscopy
- CXCL10:
-
C-X-C Motif Chemokine Ligand 10
- DAMP:
-
Damage Associated Molecular Pattern
- EAE:
-
Experimental Autoimmune Encephalomyeliti
- EGFR:
-
Epidermal Growth Factor Receptor
- ERK:
-
Extracellular signal-regulated Kinases
- EV-71:
-
Enterovirus 71
- Gal-9:
-
Galectin-9
- GAMs:
-
Glioma Associated Microglia/Macrophages
- GRPC:
-
Glial Restricted Progenitor Cell
- GSC:
-
Glioma Stem Cell
- HIF-α:
-
Hypoxia-Inducible Factor-1
- H-RAS:
-
Harvey Rat Sarcoma Virus
- IDH1/2:
-
Isocitrate Dehydrogenase ½
- IFI16:
-
Interferon Gamma Inducible Protein 16
- IL-12:
-
Interleukin 12
- IL-18:
-
Interleukin 18; IL-1β, Interleukin 1 beta
- IL-2:
-
Interleukin 2
- IL-23:
-
Interleukin 23
- IL-6:
-
Interleukin 6
- IPA:
-
Ingenuity Pathway Analysis
- JAK:
-
Janus Activated Kinase
- LGG:
-
Low Grade Glioma
- MAPK:
-
Mitogen‑Activated Protein Kinase
- MDSC:
-
Myeloid-Derived Suppressor Cells
- MGMT:
-
O-6-Methylguanine-DNA Methyltransferase
- MHC:
-
Major Histocompatibility Complex
- MS:
-
Multiple Sclerosis
- NF-κB:
-
Nuclear Factor-κB
- NG2:
-
Neuron-glial Antigen 2
- NLR:
-
Nucleotide-binding and Leucine-rich Repeat
- NLRC4:
-
NLR Family CARD Domain Containing 4
- NLRP3:
-
NLR Family Pyrin Domain Containing Protein 3
- NSC:
-
Neural Stem Cell
- OLIG2:
-
Oligodendrocyte Transcription Factor 2
- OPC:
-
Oligodendrocyte Precursor Cells
- pDC:
-
Plasmacytoid Dendritic Cell
- PDGF-AA:
-
Platelet-Derived Growth Factor AA
- PDGFRα:
-
Platelet-Derived Growth Factor Receptor A
- PNS:
-
Peripheral Nervous System
- PPAR-γ:
-
Peroxisome Proliferator-Activated Receptor γ
- PRR:
-
Pattern Recognition Receptors
- PTEN:
-
Phosphatase and Tension Homolog
- PTM:
-
Post-Translational Modification
- PYD:
-
Pyrin Domain
- PYHIN:
-
Pyrin and HIN domain-containing
- RAS:
-
Rat Sarcoma Virus
- RLR:
-
RIG-I-like Receptor
- ROS:
-
Reactive Oxygen Species
- SP1:
-
Specificity Protein 1
- SSFA2:
-
Sperm-Specific Antigen 2
- STAT3:
-
Signal Transducer and Activator of Transcription 3
- T3SS:
-
Type III Secretion System
- TCGA:
-
The Cancer Genome Atlas
- TERT:
-
Telomerase Reverse Transcriptase
- TGF- β:
-
Transforming Growth Factor-beta
- Tim-3:
-
T cell Immunoglobulin and Mucin-domain containing-3
- TIMER:
-
Tumor Immune Estimation Resource
- TLR:
-
Toll-like Receptor
- TME:
-
Tumor Microenvironment
- TNF-α:
-
Tumor Necrosis Factor-α
- TP53:
-
Tumor Protein p53
- TTFields:
-
Tumor Treating Fields
- VEGF:
-
Vascular Endothelial Growth Factor
- WHO:
-
World Health Organization
References
Ostrom QT, Bauchet L, Davis FG, et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 2014;16(7):896–913. https://doi.org/10.1093/neuonc/nou087.
Weller M, Wick W, Aldape K, et al. Glioma. Nature reviews Disease primers. Jul 16 2015;1:15017. https://doi.org/10.1038/nrdp.2015.17
Swartz MA, Iida N, Roberts EW, et al. Tumor microenvironment complexity: emerging roles in cancer therapy. Can Res. 2012;72(10):2473–80. https://doi.org/10.1158/0008-5472.can-12-0122.
Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125(Pt 23):5591–6. https://doi.org/10.1242/jcs.116392.
Litak J, Mazurek M, Grochowski C, Kamieniak P, Roliński J. PD-L1/PD-1 Axis in Glioblastoma Multiforme. International journal of molecular sciences.2019;20(21):https://doi.org/10.3390/ijms20215347
Basheer AS, Abas F, Othman I, Naidu R. Role of Inflammatory Mediators, Macrophages, and Neutrophils in Glioma Maintenance and Progression: Mechanistic Understanding and Potential Therapeutic Applications. Cancers. 2021;13(16):4226.
Iwami K, Natsume A, Wakabayashi T. Cytokine networks in glioma. Neurosurgical review. Jul 2011;34(3):253–63; discussion 263–4. https://doi.org/10.1007/s10143-011-0320-y
Solinas G, Marchesi F, Garlanda C, Mantovani A, Allavena P. Inflammation-mediated promotion of invasion and metastasis. Cancer Metastasis Rev. 2010;29(2):243–8. https://doi.org/10.1007/s10555-010-9227-2.
Lin W, Gao J, Zhang H, et al. Identification of molecular subtypes based on inflammatory response in lower-grade glioma. Inflammation and Regeneration. 2022/10/01 2022;42(1):29. https://doi.org/10.1186/s41232-022-00215-9
Alghamri MS, McClellan BL, Hartlage CS, et al. Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments. Frontiers in pharmacology. 2021;12:680021. https://doi.org/10.3389/fphar.2021.680021
Missiroli S, Perrone M, Boncompagni C, et al. Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer. Cancers (Basel). May 11 2021;13(10). https://doi.org/10.3390/cancers13102297
Rolim GB, Dantas Lima AJP, dos Santos Cardoso VI, et al. Can inflammasomes promote the pathophysiology of glioblastoma multiforme? A view about the potential of the anti-inflammasome therapy as pharmacological target. Critical Reviews in Oncology/Hematology. 2022/04/01/ 2022;172:103641. https://doi.org/10.1016/j.critrevonc.2022.103641
Posti JP, Bori M, Kauko T, et al. Presenting symptoms of glioma in adults. Acta Neurol Scand. 2015;131(2):88–93. https://doi.org/10.1111/ane.12285.
Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nature Reviews Clinical Oncology. 2021/03/01 2021;18(3):170–186. https://doi.org/10.1038/s41571-020-00447-z
Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231–51. https://doi.org/10.1093/neuonc/noab106.
Stoyanov GS, Lyutfi E, Georgieva R, et al. Reclassification of Glioblastoma Multiforme According to the 2021 World Health Organization Classification of Central Nervous System Tumors: A Single Institution Report and Practical Significance. Cureus. Feb 2022;14(2):e21822. https://doi.org/10.7759/cureus.21822
Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157–73. https://doi.org/10.1016/j.ccr.2006.02.019.
Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. https://doi.org/10.1016/j.ccr.2009.12.020.
Zhao Z, Zhang KN, Wang Q, et al. Chinese Glioma Genome Atlas (CGGA): A Comprehensive Resource with Functional Genomic Data from Chinese Glioma Patients. Genomics Proteomics Bioinformatics. 2021;19(1):1–12. https://doi.org/10.1016/j.gpb.2020.10.005.
Chaligne R, Gaiti F, Silverbush D, et al. Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states. Nature Genetics. 2021/10/01 2021;53(10):1469–1479. https://doi.org/10.1038/s41588-021-00927-7
Cohen AL, Holmen SL, Colman H. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 2013;13(5):345. https://doi.org/10.1007/s11910-013-0345-4.
Mizoguchi M, Yoshimoto K, Ma X, et al. Molecular characteristics of glioblastoma with 1p/19q co-deletion. Brain Tumor Pathol. 2012;29(3):148–53. https://doi.org/10.1007/s10014-012-0107-z.
Chen R, Smith-Cohn M, Cohen AL, Colman H. Glioma Subclassifications and Their Clinical Significance. Neurotherapeutics. 2017;14(2):284–97. https://doi.org/10.1007/s13311-017-0519-x.
Sidaway P. Glioblastoma subtypes revisited. Nature Reviews Clinical Oncology. 2017/10/01 2017;14(10):587–587. https://doi.org/10.1038/nrclinonc.2017.122
Cahill DP, Sloan AE, Nahed BV, et al. The role of neuropathology in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. J Neurooncol. 2015;125(3):531–49. https://doi.org/10.1007/s11060-015-1909-8.
Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK. Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer. 1997;79(7):1381–93. https://doi.org/10.1002/(sici)1097-0142(19970401)79:7%3c1381::aid-cncr16%3e3.0.co;2-w.
Alderton GK. The origins of glioma. Nature Reviews Cancer. 2011/09/01 2011;11(9):627–627. https://doi.org/10.1038/nrc3129
Sanai N, Alvarez-Buylla A, Berger MS. Neural Stem Cells and the Origin of Gliomas. N Engl J Med. 2005;353(8):811–22. https://doi.org/10.1056/NEJMra043666.
Geha S, Pallud J, Junier MP, et al. NG2+/Olig2+ cells are the major cycle-related cell population of the adult human normal brain. Brain Pathology (Zurich, Switzerland). 2010;20(2):399–411. https://doi.org/10.1111/j.1750-3639.2009.00295.x.
Dawson MR, Polito A, Levine JM, Reynolds R. NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol Cell Neurosci. 2003;24(2):476–88. https://doi.org/10.1016/s1044-7431(03)00210-0.
Rhee W, Ray S, Yokoo H, et al. Quantitative analysis of mitotic Olig2 cells in adult human brain and gliomas: implications for glioma histogenesis and biology. Glia. 2009;57(5):510–23. https://doi.org/10.1002/glia.20780.
Jones TR, Bigner SH, Schold SC Jr, Eng LF, Bigner DD. Anaplastic human gliomas grown in athymic mice. Morphology and glial fibrillary acidic protein expression. Am J Pathol. 1981;105(3):316–27.
Dufour C, Cadusseau J, Varlet P, et al. Astrocytes reverted to a neural progenitor-like state with transforming growth factor alpha are sensitized to cancerous transformation. Stem cells (Dayton, Ohio). 2009;27(10):2373–82. https://doi.org/10.1002/stem.155.
Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002;1(3):269–77. https://doi.org/10.1016/s1535-6108(02)00046-6.
Ding H, Roncari L, Shannon P, et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Can Res. 2001;61(9):3826–36.
Jiang Y, Uhrbom L. On the origin of glioma. Upsala J Med Sci. 2012;117(2):113–21. https://doi.org/10.3109/03009734.2012.658976.
Baghban R, Roshangar L, Jahanban-Esfahlan R, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Communication and Signaling. 2020/04/07 2020;18(1):59. https://doi.org/10.1186/s12964-020-0530-4
Wen PY, Kesari S. Malignant Gliomas in Adults. N Engl J Med. 2008;359(5):492–507. https://doi.org/10.1056/NEJMra0708126.
Friedmann-Morvinski D. Glioblastoma heterogeneity and cancer cell plasticity. Crit Rev Oncog. 2014;19(5):327–36. https://doi.org/10.1615/critrevoncog.2014011777.
Pombo Antunes AR, Scheyltjens I, Duerinck J, Neyns B, Movahedi K, Van Ginderachter JA. Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. eLife. 2020/02/04 2020;9:e52176. https://doi.org/10.7554/eLife.52176
Barthel L, Hadamitzky M, Dammann P, et al. Glioma: molecular signature and crossroads with tumor microenvironment. Cancer and Metastasis Reviews. 2022/03/01 2022;41(1):53–75. https://doi.org/10.1007/s10555-021-09997-9
Shabtay-Orbach A, Amit M, Binenbaum Y, Na’ara S, Gil Z. Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor. Int J Cancer. 2015;137(5):1012–20. https://doi.org/10.1002/ijc.29380.
Hoelzinger DB, Demuth T, Berens ME. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J Natl Cancer Inst. 2007;99(21):1583–93. https://doi.org/10.1093/jnci/djm187.
Shen Y, Grisdale CJ, Islam SA, et al. Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments. Proc Natl Acad Sci. 2019;116(38):19098–108. https://doi.org/10.1073/pnas.1813495116.
Norden AD, Wen PY. Glioma therapy in adults. Neurologist. 2006;12(6):279–92. https://doi.org/10.1097/01.nrl.0000250928.26044.47.
Yang K, Wu Z, Zhang H, et al. Glioma targeted therapy: insight into future of molecular approaches. Molecular Cancer. 2022/02/08 2022;21(1):39. https://doi.org/10.1186/s12943-022-01513-z
Couturier CP, Ayyadhury S, Le PU, et al. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nature Communications. 2020/07/08 2020;11(1):3406. https://doi.org/10.1038/s41467-020-17186-5
Patel AP, Tirosh I, Trombetta JJ, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396–401. https://doi.org/10.1126/science.1254257.
Abdelfattah N, Kumar P, Wang C, et al. Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target. Nature Communications. 2022/02/09 2022;13(1):767. https://doi.org/10.1038/s41467-022-28372-y
Neftel C, Laffy J, Filbin MG, et al. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell. 2019/08/08/ 2019;178(4):835–849.e21. https://doi.org/10.1016/j.cell.2019.06.024
Im S, Hyeon J, Rha E, et al. Classification of Diffuse Glioma Subtype from Clinical-Grade Pathological Images Using Deep Transfer Learning. Sensors (Basel, Switzerland). May 17 2021;21(10). https://doi.org/10.3390/s21103500
Behnan J, Finocchiaro G, Hanna G. The landscape of the mesenchymal signature in brain tumours. Brain. 2019;142(4):847–66. https://doi.org/10.1093/brain/awz044.
Azam Z, TO S-ST, Tannous BA. Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance. Advanced Science. 2020;7(22):2002015. https://doi.org/10.1002/advs.202002015
Wang L, Babikir H, Müller S, et al. The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation. Cancer Discov. 2019;9(12):1708–19. https://doi.org/10.1158/2159-8290.cd-19-0329.
Coy S, Wang S, Stopka SA, et al. Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma. Nature Communications. 2022/08/16 2022;13(1):4814. https://doi.org/10.1038/s41467-022-32430-w
Ravi VM, Will P, Kueckelhaus J, et al. Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma. Cancer cell. 2022/06/13/ 2022;40(6):639–655.e13. https://doi.org/10.1016/j.ccell.2022.05.009
Murphy JB, Sturm E. CONDITIONS DETERMINING THE TRANSPLANTABILITY OF TISSUES IN THE BRAIN. J Exp Med. 1923;38(2):183–97. https://doi.org/10.1084/jem.38.2.183.
Fabry Z, Schreiber HA, Harris MG, Sandor M. Sensing the microenvironment of the central nervous system: immune cells in the central nervous system and their pharmacological manipulation. Curr Opin Pharmacol. 2008;8(4):496–507. https://doi.org/10.1016/j.coph.2008.07.009.
Wekerle H. Breaking ignorance: the case of the brain. Curr Top Microbiol Immunol. 2006;305:25–50. https://doi.org/10.1007/3-540-29714-6_2.
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1–12. https://doi.org/10.1016/j.bbi.2016.03.010.
Galvão RP, Zong H. Inflammation and Gliomagenesis: Bi-Directional Communication at Early and Late Stages of Tumor Progression. Curr Pathobiology Rep. 2013;1(1):19–28. https://doi.org/10.1007/s40139-012-0006-3.
Da Ros M, De Gregorio V, Iorio AL, et al. Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier. International journal of molecular sciences. 2018;19(10). https://doi.org/10.3390/ijms19102879
Erickson MA, Dohi K, Banks WA. Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier. NeuroImmunoModulation. 2012;19(2):121–30. https://doi.org/10.1159/000330247.
Erdő F, Denes L, de Lange E. Age-associated physiological and pathological changes at the blood-brain barrier: A review. J Cereb Blood Flow Metab. 2017;37(1):4–24. https://doi.org/10.1177/0271678x16679420.
Kore RA, Abraham EC. Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells. Biochem Biophys Res Commun. 2014;453(3):326–31. https://doi.org/10.1016/j.bbrc.2014.09.068.
Belykh E, Shaffer KV, Lin C, Byvaltsev VA, Preul MC, Chen L. Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors. Front Oncol. 2020;10:739. https://doi.org/10.3389/fonc.2020.00739.
Könnecke H, Bechmann I. The role of microglia and matrix metalloproteinases involvement in neuroinflammation and gliomas. Clinical & developmental immunology. 2013;2013:914104. https://doi.org/10.1155/2013/914104
Luo H, Shusta EV. Blood-Brain Barrier Modulation to Improve Glioma Drug Delivery. Pharmaceutics. 2020;12(11):1085.
Lim J, Park Y, Ahn JW, et al. Autologous adoptive immune-cell therapy elicited a durable response with enhanced immune reaction signatures in patients with recurrent glioblastoma: An open label, phase I/IIa trial. PLOS ONE. 2021;16(3):e0247293. https://doi.org/10.1371/journal.pone.0247293
Liu H, Sun Y, Zhang Q, et al. Pro-inflammatory and proliferative microglia drive progression of glioblastoma. Cell reports. Sep 14 2021;36(11):109718. https://doi.org/10.1016/j.celrep.2021.109718
Zeiner PS, Preusse C, Golebiewska A, et al. Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas. Brain pathology (Zurich, Switzerland). 2019;29(4):513–29. https://doi.org/10.1111/bpa.12690.
Semple BD, Kossmann T, Morganti-Kossmann MC. Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab. 2010;30(3):459–73. https://doi.org/10.1038/jcbfm.2009.240.
Brandenburg S, Müller A, Turkowski K, et al. Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol. 2016;131(3):365–78. https://doi.org/10.1007/s00401-015-1529-6.
Fu W, Wang W, Li H, et al. Single-Cell Atlas Reveals Complexity of the Immunosuppressive Microenvironment of Initial and Recurrent Glioblastoma. Front Immunol. 2020;11:835. https://doi.org/10.3389/fimmu.2020.00835.
Ma K, Guo Q, Zhang X, Li Y. High Expression of Triggering Receptor Expressed on Myeloid Cells 1 Predicts Poor Prognosis in Glioblastoma. Onco Targets Ther. 2023;16:331–45. https://doi.org/10.2147/ott.s407892.
Jackson C, Cherry C, Bom S, et al. Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma. bioRxiv : the preprint server for biology. Mar 27 2023;https://doi.org/10.1101/2023.03.26.534192
Miyazaki T, Ishikawa E, Sugii N, Matsuda M. Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment. Cancers (Basel). 2020;12(7). https://doi.org/10.3390/cancers12071960
Mi Y, Guo N, Luan J, et al. The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment. Front Immunol. 2020;11:737. https://doi.org/10.3389/fimmu.2020.00737.
Chang AL, Miska J, Wainwright DA, et al. CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. Can Res. 2016;76(19):5671–82. https://doi.org/10.1158/0008-5472.can-16-0144.
Pfrieger FW, Barres BA. Synaptic Efficacy Enhanced by Glial Cells in Vitro. Science. 1997;277(5332):1684–7. https://doi.org/10.1126/science.277.5332.1684.
Guttenplan KA, Liddelow SA. Astrocytes and microglia: Models and tools. J Exp Med. 2018;216(1):71–83. https://doi.org/10.1084/jem.20180200.
Liu C, Zhao XM, Wang Q, et al. Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy. J Neuroinflammation. 2023;20(1):161. https://doi.org/10.1186/s12974-023-02840-8
Giovannoni F, Quintana FJ. The Role of Astrocytes in CNS Inflammation. Trends Immunol. 2020;41(9):805–19. https://doi.org/10.1016/j.it.2020.07.007.
An JR, Liu JT, Gao XM, et al. Effects of liraglutide on astrocyte polarization and neuroinflammation in db/db mice: focus on iron overload and oxidative stress. Front Cell Neurosci. 2023;17:1136070. https://doi.org/10.3389/fncel.2023.1136070.
Roesler R, Dini SA, Isolan GR. Neuroinflammation and immunoregulation in glioblastoma and brain metastases: Recent developments in imaging approaches. Clin Exp Immunol. 2021;206(3):314–24. https://doi.org/10.1111/cei.13668.
Kaur N, Chugh H, Sakharkar MK, Dhawan U, Chidambaram SB, Chandra R. Neuroinflammation Mechanisms and Phytotherapeutic Intervention: A Systematic Review. ACS Chemical Neuroscience. 2020/11/18 2020;11(22):3707–3731. https://doi.org/10.1021/acschemneuro.0c00427
Martinon F, Burns K, Tschopp J. The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-β. Molecular Cell. 2002/08/01/ 2002;10(2):417–426. https://doi.org/10.1016/S1097-2765(02)00599-3
Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–20. https://doi.org/10.1038/nri.2016.58.
Wu J, Chen ZJ. Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol. 2014;32:461–88. https://doi.org/10.1146/annurev-immunol-032713-120156.
Snodgrass RG, Huang S, Choi IW, Rutledge JC, Hwang DH. Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. Journal of immunology (Baltimore, Md : 1950). 2013;191(8):4337–47. https://doi.org/10.4049/jimmunol.1300298
Bai L, Li W, Zheng W, Xu D, Chen N, Cui J. Promising targets based on pattern recognition receptors for cancer immunotherapy. Pharmacological Research. 2020/09/01/ 2020;159:105017. https://doi.org/10.1016/j.phrs.2020.105017
Shekarian T, Valsesia-Wittmann S, Brody J, et al. Pattern recognition receptors: immune targets to enhance cancer immunotherapy. Annals of Oncology. 2017/08/01/ 2017;28(8):1756–1766. https://doi.org/10.1093/annonc/mdx179
Vinnakota K, Hu F, Ku MC, et al. Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion. Neuro Oncol. 2013;15(11):1457–68. https://doi.org/10.1093/neuonc/not115.
Jiang Y, Zhou J, Luo P, et al. Prosaposin promotes the proliferation and tumorigenesis of glioma through toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway. EBioMedicine. 2018;37:78–90. https://doi.org/10.1016/j.ebiom.2018.10.053.
Gieryng A, Pszczolkowska D, Walentynowicz KA, Rajan WD, Kaminska B. Immune microenvironment of gliomas. Laboratory investigation; a journal of technical methods and pathology. 2017;97(5):498–518. https://doi.org/10.1038/labinvest.2017.19
Triller P, Bachorz J, Synowitz M, Kettenmann H, Markovic D. O-Vanillin Attenuates the TLR2 Mediated Tumor-Promoting Phenotype of Microglia.Int J Mol Sci. 2020;21(8). https://doi.org/10.3390/ijms21082959
Hu F, Ku MC, Markovic D, et al. Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. Int J Cancer. 2014;135(11):2569–78. https://doi.org/10.1002/ijc.28908.
Huang Y, Zhang B, Haneke H, et al. Glial cell line-derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia-mediated glioma progression. J Neurosci Res. 2021;99(4):1048–63. https://doi.org/10.1002/jnr.24768.
Qian J, Luo F, Yang J, et al. TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia. Cancer Immunol Res. 2018;6(10):1220–33. https://doi.org/10.1158/2326-6066.cir-18-0020.
Huang Y, Zhang Q, Lubas M, et al. Synergistic Toll-like Receptor 3/9 Signaling Affects Properties and Impairs Glioma-Promoting Activity of Microglia. J Neurosci. 2020;40(33):6428–43. https://doi.org/10.1523/jneurosci.0666-20.2020.
Li L, Acioglu C, Heary RF, Elkabes S. Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behav Immun. 2021;91:740–55. https://doi.org/10.1016/j.bbi.2020.10.007.
Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15(7):e257–67. https://doi.org/10.1016/s1470-2045(13)70585-0.
Megjugorac NJ, Young HA, Amrute SB, Olshalsky SL, Fitzgerald-Bocarsly P. Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells. J Leukoc Biol. 2004;75(3):504–14. https://doi.org/10.1189/jlb.0603291.
Mitchell D, Chintala S, Dey M. Plasmacytoid dendritic cell in immunity and cancer. J Neuroimmunol. 2018;322:63–73. https://doi.org/10.1016/j.jneuroim.2018.06.012.
Curtin JF, Liu N, Candolfi M, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS medicine. 2009;6(1):e10. https://doi.org/10.1371/journal.pmed.1000010
Hu J, Shi B, Liu X, et al. The activation of Toll-like receptor 4 reverses tumor differentiation in human glioma U251 cells via Notch pathway. Int Immunopharmacol. 2018;64:33–41. https://doi.org/10.1016/j.intimp.2018.08.019.
Wang F, Zhang P, Yang L, et al. Activation of toll-like receptor 2 promotes invasion by upregulating MMPs in glioma stem cells. Am J Transl Res. 2015;7(3):607–15.
Puliyappadamba VT, Hatanpaa KJ, Chakraborty S, Habib AA. The role of NF-κB in the pathogenesis of glioma. Molecular & cellular oncology. Jul-Sep 2014;1(3):e963478. https://doi.org/10.4161/23723548.2014.963478
Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37. https://doi.org/10.1038/nri2873.
Guo H, Callaway JB, Ting JPY. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature Medicine. 2015/07/01 2015;21(7):677–687. https://doi.org/10.1038/nm.3893
Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nature Reviews Immunology. 2016/07/01 2016;16(7):407–420. https://doi.org/10.1038/nri.2016.58
Kast RE. The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs-disulfiram and ritonavir. Chin J Cancer. 2015;34(4):161–5. https://doi.org/10.1186/s40880-015-0010-1.
Tarassishin L, Casper D, Lee SC. Aberrant Expression of Interleukin-1β and Inflammasome Activation in Human Malignant Gliomas. PLOS ONE. 2014;9(7):e103432. https://doi.org/10.1371/journal.pone.0103432
Tong L, Xie C, Wei Y, et al. Antitumor Effects of Berberine on Gliomas via Inactivation of Caspase-1-Mediated IL-1β and IL-18 Release. Front Oncol. 2019;9:364. https://doi.org/10.3389/fonc.2019.00364.
Downs KP, Nguyen H, Dorfleutner A, Stehlik C. An overview of the non-canonical inflammasome. Molecular Aspects of Medicine. 2020/12/01/ 2020;76:100924. https://doi.org/10.1016/j.mam.2020.100924
Govindarajan V, de Rivero Vaccari JP, Keane RW. Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets. J Neuroinflammation. 2020/09/02 2020;17(1):260. https://doi.org/10.1186/s12974-020-01944-9
Cyr B, Hadad R, Keane RW, de Rivero Vaccari JP. The Role of Non-canonical and Canonical Inflammasomes in Inflammaging. Frontiers in molecular neuroscience. 2022;15:774014. https://doi.org/10.3389/fnmol.2022.774014
Zhang M, Cheng Y, Xue Z, Sun Q, Zhang J. A novel pyroptosis-related gene signature predicts the prognosis of glioma through immune infiltration. BMC Cancer. 2021/12/07 2021;21(1):1311. https://doi.org/10.1186/s12885-021-09046-2
Liu J, Gao L, Zhu X, et al. Gasdermin D Is a Novel Prognostic Biomarker and Relates to TMZ Response in Glioblastoma. Cancers. 2021;13(22):5620.
Zi H, Tuo Z, He Q, et al. Comprehensive Bioinformatics Analysis of Gasdermin Family of Glioma. Computational Intelligence and Neuroscience. 2022/04/15 2022;2022:9046507. https://doi.org/10.1155/2022/9046507
Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology. 2019/08/01 2019;19(8):477–489. https://doi.org/10.1038/s41577-019-0165-0
Li L, Liu Y. Aging-related gene signature regulated by Nlrp3 predicts glioma progression. Am J Cancer Res. 2015;5(1):442–9.
Yin XF, Zhang Q, Chen ZY, et al. NLRP3 in human glioma is correlated with increased WHO grade, and regulates cellular proliferation, apoptosis and metastasis via epithelial-mesenchymal transition and the PTEN/AKT signaling pathway. Int J Oncol. 2018;53(3):973–86. https://doi.org/10.3892/ijo.2018.4480.
Tricarico PM, Epate A, Celsi F, Crovella S. Alendronate treatment induces IL-1B expression and apoptosis in glioblastoma cell line. Inflammopharmacology. 2018/02/01 2018;26(1):285–290. https://doi.org/10.1007/s10787-017-0369-5
Xue L, Lu B, Gao B, et al. NLRP3 Promotes Glioma Cell Proliferation and Invasion via the Interleukin-1β/NF-κB p65 Signals. Oncol Res. 2019;27(5):557–64. https://doi.org/10.3727/096504018x15264647024196.
Gong Z, Gao X, Yang Q, et al. Phosphorylation of ERK-Dependent NF-κB Triggers NLRP3 Inflammasome Mediated by Vimentin in EV71-Infected Glioblastoma Cells. Molecules (Basel, Switzerland). Jun 29 2022;27(13). https://doi.org/10.3390/molecules27134190
Shang S, Wang L, Zhang Y, Lu H, Lu X. The Beta-Hydroxybutyrate Suppresses the Migration of Glioma Cells by Inhibition of NLRP3 Inflammasome. Cellular and Molecular Neurobiology. 2018/11/01 2018;38(8):1479–1489. https://doi.org/10.1007/s10571-018-0617-2
Honda S, Sadatomi D, Yamamura Y, Nakashioya K, Tanimura S, Takeda K. WP1066 suppresses macrophage cell death induced by inflammasome agonists independently of its inhibitory effect on STAT3. Cancer Sci. 2017;108(3):520–7. https://doi.org/10.1111/cas.13154.
Dos Santos DC, Rafique J, Saba S, et al. IP-Se-06, a Selenylated Imidazo[1,2-a]pyridine, Modulates Intracellular Redox State and Causes Akt/mTOR/HIF-1α and MAPK Signaling Inhibition, Promoting Antiproliferative Effect and Apoptosis in Glioblastoma Cells. Oxid Med Cell Longev. 2022;2022:3710449. https://doi.org/10.1155/2022/3710449.
Li Z, Fu W-J, Chen X-Q, et al. Autophagy-based unconventional secretion of HMGB1 in glioblastoma promotes chemosensitivity to temozolomide through macrophage M1-like polarization. J Experimental Clin Cancer Res. 2022/02/22 2022;41(1):74. https://doi.org/10.1186/s13046-022-02291-8
Altinoz MA, Elmaci İ, Hacimuftuoglu A, Ozpinar A, Hacker E, Ozpinar A. PPARδ and its ligand erucic acid may act anti-tumoral, neuroprotective, and myelin protective in neuroblastoma, glioblastoma, and Parkinson's disease. Molecular Aspects of Medicine. 2021/04/01/ 2021;78:100871. https://doi.org/10.1016/j.mam.2020.100871
Poyet J-L, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES. Identification of Ipaf, a Human Caspase-1-activating Protein Related to Apaf-1*.J Biol Chem. 2001/07/27/ 2001;276(30):28309–28313. https://doi.org/10.1074/jbc.C100250200
Mariathasan S, Newton K, Monack DM, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004/07/01 2004;430(6996):213–218. https://doi.org/10.1038/nature02664
Franchi L, Amer A, Body-Malapel M, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nature Immunology. 2006/06/01 2006;7(6):576–582. https://doi.org/10.1038/ni1346
Duncan JA, Canna SW. The NLRC4 Inflammasome. Immunol Rev. 2018;281(1):115–23. https://doi.org/10.1111/imr.12607.
Wen J, Xuan B, Liu Y, et al. Updating the NLRC4 Inflammasome: from Bacterial Infections to Autoimmunity and Cancer. Review. Frontiers in immunology. 2021-June-30 2021;12. https://doi.org/10.3389/fimmu.2021.702527
Man SM, Hopkins LJ, Nugent E, et al. Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex. Proc Natl Acad Sci. 2014;111(20):7403–8. https://doi.org/10.1073/pnas.1402911111.
Tenthorey JL, Chavez RA, Thompson TW, Deets KA, Vance RE, Rauch I. NLRC4 inflammasome activation is NLRP3- and phosphorylation-independent during infection and does not protect from melanoma. Journal of Experimental Medicine. 2020;217(7). https://doi.org/10.1084/jem.20191736
Lim J, Kim MJ, Park Y, et al. Upregulation of the NLRC4 inflammasome contributes to poor prognosis in glioma patients. Scientific Reports. 2019/05/27 2019;9(1):7895. https://doi.org/10.1038/s41598-019-44261-9
Sharma N, Saxena S, Agrawal I, et al. Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma. Scientific Reports. 2019/06/11 2019;9(1):8480. https://doi.org/10.1038/s41598-019-44854-4
Sim J, Park J, Kim S, et al. Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome. Int J Mol Sci. 2022;23(4). https://doi.org/10.3390/ijms23042028
Souza COS, Ketelut-Carneiro N, Milanezi CM, Faccioli LH, Gardinassi LG, Silva JS. NLRC4 inhibits NLRP3 inflammasome and abrogates effective antifungal CD8(+) T cell responses. iScience. 2021;24(6):102548. https://doi.org/10.1016/j.isci.2021.102548
Freeman L, Guo H, David CN, Brickey WJ, Jha S, Ting JP. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med. 2017;214(5):1351–70. https://doi.org/10.1084/jem.20150237.
Alippe Y, Kress D, Ricci B, et al. Actions of the NLRP3 and NLRC4 inflammasomes overlap in bone resorption. The FASEB Journal. 2021;35(9):e21837. https://doi.org/10.1096/fj.202100767RR
Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell. 2014;157(5):1013–22. https://doi.org/10.1016/j.cell.2014.04.007.
Shen C, Lu A, Xie WJ, et al. Molecular mechanism for NLRP6 inflammasome assembly and activation. Proc Natl Acad Sci USA. 2019;116(6):2052–7. https://doi.org/10.1073/pnas.1817221116.
Angosto-Bazarra D, Molina-López C, Pelegrín P. Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles. Communications biology. J 2022;5(1):524. https://doi.org/10.1038/s42003-022-03491-w
Yu Y, Cao F, Xiong Y, Zhou H. SP1 transcriptionally activates NLRP6 inflammasome and induces immune evasion and radioresistance in glioma cells. International immunopharmacology. 2021;98:107858. https://doi.org/10.1016/j.intimp.2021.107858
Nie H, Hu Y, Guo W, et al. miR-331-3p Inhibits Inflammatory Response after Intracerebral Hemorrhage by Directly Targeting NLRP6. Biomed Res Int. 2020;2020:6182464. https://doi.org/10.1155/2020/6182464.
Zheng D, Kern L, Elinav E. The NLRP6 inflammasome. Immunology. 2021;162(3):281–9. https://doi.org/10.1111/imm.13293.
Janani C, Ranjitha Kumari BD. PPAR gamma gene–a review. Diabetes Metabolic Syndrome. 2015;9(1):46–50. https://doi.org/10.1016/j.dsx.2014.09.015.
Kempster SL, Belteki G, Forhead AJ, et al. Developmental control of the Nlrp6 inflammasome and a substrate, IL-18, in mammalian intestine. Am J Physiol Gastrointest Liver Physiol. 2011;300(2):G253–63. https://doi.org/10.1152/ajpgi.00397.2010.
Hua TNM, Oh J, Kim S, et al. Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients. Exp Mol Med. 2020;52(4):629–42. https://doi.org/10.1038/s12276-020-0413-1.
Vladimer GI, Weng D, Paquette SW, et al. The NLRP12 inflammasome recognizes Yersinia pestis. Immunity. 2012;37(1):96–107. https://doi.org/10.1016/j.immuni.2012.07.006.
Wang HF. NLRP12-associated systemic autoinflammatory diseases in children. Pediatric rheumatology online journal. 2022;20(1):9. https://doi.org/10.1186/s12969-022-00669-8
Tuncer S, Fiorillo MT, Sorrentino R. The multifaceted nature of NLRP12. J Leukoc Biol. 2014;96(6):991–1000. https://doi.org/10.1189/jlb.3RU0514-265RR.
Zaki H, Udden SMN. The NOD-like receptor NLRP12 plays a critical role in hepatic inflammation and cancer. J Immunol. 2019;202(1 Supplement):194–44.
Tuladhar S, Kanneganti T-D. NLRP12 in innate immunity and inflammation. Molecular Aspects of Medicine. 2020/12/01/ 2020;76:100887. https://doi.org/10.1016/j.mam.2020.100887
Sharma N, Saxena S, Agrawal I, et al. Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma. Sci Rep. 2019;9(1):8480. https://doi.org/10.1038/s41598-019-44854-4
Zhu A, Li X, Wu H, et al. Molecular mechanism of SSFA2 deletion inhibiting cell proliferation and promoting cell apoptosis in glioma. Pathology - Research and Practice. 2019/03/01/ 2019;215(3):600–606. https://doi.org/10.1016/j.prp.2018.12.035
Ulland TK, Jain N, Hornick EE, et al. Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nature Communications. 2016/10/25 2016;7(1):13180. https://doi.org/10.1038/ncomms13180
Muruve DA, Pétrilli V, Zaiss AK, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452(7183):103–7. https://doi.org/10.1038/nature06664.
Wang B, Yin Q. AIM2 inflammasome activation and regulation: A structural perspective. J Struct Biol. 2017;200(3):279–82. https://doi.org/10.1016/j.jsb.2017.08.001.
Bürckstümmer T, Baumann C, Blüml S, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009;10(3):266–72. https://doi.org/10.1038/ni.1702.
Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458(7237):509–13. https://doi.org/10.1038/nature07710.
Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458(7237):514–8. https://doi.org/10.1038/nature07725.
Ablasser A, Gulen MF. The role of cGAS in innate immunity and beyond. J Mol Med (Berl). 2016;94(10):1085–93. https://doi.org/10.1007/s00109-016-1423-2.
Sagulenko V, Thygesen SJ, Sester DP, et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ. 2013;20(9):1149–60. https://doi.org/10.1038/cdd.2013.37.
Di Micco A, Frera G, Lugrin J, et al. AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity. Proc Natl Acad Sci USA. 2016;113(32):E4671–80. https://doi.org/10.1073/pnas.1602419113.
Sagulenko V, Thygesen SJ, Sester DP, et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death & Differentiation. 2013/09/01 2013;20(9):1149–1160. https://doi.org/10.1038/cdd.2013.37
Li Z, Shi X, Li H, Wang W, Li X. Low expression of AIM2 combined with high expression of p-STAT3 is associated with poor prognosis in hypopharyngeal squamous cell carcinoma. Oncol Rep. 2019;41(4):2396–408. https://doi.org/10.3892/or.2019.7029.
Kim H, Seo JS, Lee S-Y, et al. AIM2 inflammasome contributes to brain injury and chronic post-stroke cognitive impairment in mice. Brain, behavior, and immunity. 2020/07/01/ 2020;87:765–776. https://doi.org/10.1016/j.bbi.2020.03.011
Chen PA, Shrivastava G, Balcom EF, et al. Absent in melanoma 2 regulates tumor cell proliferation in glioblastoma multiforme. J Neurooncol. 2019;144(2):265–73. https://doi.org/10.1007/s11060-019-03230-y.
Barclay WE, Aggarwal N, Deerhake ME, et al. The AIM2 inflammasome is activated in astrocytes during the late phase of EAE. JCI Insight. 04/22/ 2022;7(8). https://doi.org/10.1172/jci.insight.155563
Chen D, Le SB, Hutchinson TE, et al. Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma. The Journal of Clinical Investigation. 04/15/ 2022;132(8). https://doi.org/10.1172/JCI149258
Španić E, Langer Horvat L, Ilić K, Hof PR, Šimić G. NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer and Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss. Cells. 2022;11(14):2223.
Shen E, Han Y, Cai C, et al. Low expression of NLRP1 is associated with a poor prognosis and immune infiltration in lung adenocarcinoma patients. Aging. 2021;13(5):7570–88. https://doi.org/10.18632/aging.202620.
Zhai Z, Samson JM, Yamauchi T, et al. Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma. Cancers (Basel). 2020;12(9). https://doi.org/10.3390/cancers12092518
Wang J, Wakeman TP, Lathia JD, et al. Notch promotes radioresistance of glioma stem cells. Stem cells (Dayton, Ohio). 2010;28(1):17–28. https://doi.org/10.1002/stem.261.
Capaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 2013;34(7):1420–30. https://doi.org/10.1093/carcin/bgt127.
Martz CA, Ottina KA, Singleton KR, et al. Systematic identification of signaling pathways with potential to confer anticancer drug resistance. Science signaling. 2014;7(357):ra121. https://doi.org/10.1126/scisignal.aaa1877
Nair JS, Sheikh T, Ho AL, Schwartz GK. PTEN regulates sensitivity of melanoma cells to RO4929097, the γ-secretase inhibitor. Anticancer Res. 2013;33(4):1307–16.
Carriere J, Dorfleutner A, Stehlik C. NLRP7: From inflammasome regulation to human disease. Immunology. 2021;163(4):363–76. https://doi.org/10.1111/imm.13372.
Christgen S, Place DE, Kanneganti T-D. Toward targeting inflammasomes: insights into their regulation and activation. Cell Research. 2020/04/01 2020;30(4):315–327. https://doi.org/10.1038/s41422-020-0295-8
Fan T, Wan Y, Niu D, et al. Comprehensive analysis of pyroptosis regulation patterns and their influence on tumor immune microenvironment and patient prognosis in glioma. Discover Oncology. 2022/03/10 2022;13(1):13. https://doi.org/10.1007/s12672-022-00474-5
Minkiewicz J, de Rivero Vaccari JP, Keane RW. Human astrocytes express a novel NLRP2 inflammasome. Glia. 2013;61(7):1113–21. https://doi.org/10.1002/glia.22499.
Alivand MR, Najafi S, Esmaeili S, Rahmanpour D, Zhaleh H, Rahmati Y. Integrative analysis of DNA methylation and gene expression profiles to identify biomarkers of glioblastoma. Cancer Genet. 2021;258–259:135–50. https://doi.org/10.1016/j.cancergen.2021.10.008.
Sarrazy V, Vedrenne N, Billet F, et al. TLR4 signal transduction pathways neutralize the effect of Fas signals on glioblastoma cell proliferation and migration. Cancer Lett. 2011;311(2):195–202. https://doi.org/10.1016/j.canlet.2011.07.018.
Grauer OM, Molling JW, Bennink E, et al. TLR ligands in the local treatment of established intracerebral murine gliomas. Journal of immunology (Baltimore, Md : 1950). 2008;181(10):6720–9. https://doi.org/10.4049/jimmunol.181.10.6720
Niranjan R, Nagarajan R, Hanif K, Nath C, Shukla R. LPS induces mediators of neuroinflammation, cell proliferation, and GFAP expression in human astrocytoma cells U373MG: the anti-inflammatory and anti-proliferative effect of guggulipid. Neurol Sci. 2014;35(3):409–14. https://doi.org/10.1007/s10072-013-1530-6.
Che F, Yin J, Quan Y, et al. TLR4 interaction with LPS in glioma CD133+ cancer stem cells induces cell proliferation, resistance to chemotherapy and evasion from cytotoxic T lymphocyte-induced cytolysis. Oncotarget. 2017;8(32):53495–507. https://doi.org/10.18632/oncotarget.18586.
Moretti IF, Lerario AM, Trombetta-Lima M, et al. Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes. Scientific Reports. 2021/01/14 2021;11(1):1333. https://doi.org/10.1038/s41598-020-79356-1
Li C, Ma L, Liu Y, et al. TLR2 promotes development and progression of human glioma via enhancing autophagy. Gene. 2019;700:52–9. https://doi.org/10.1016/j.gene.2019.02.084.
Tewari R, Choudhury SR, Ghosh S, Mehta VS, Sen E. Involvement of TNFα-induced TLR4-NF-κB and TLR4-HIF-1α feed-forward loops in the regulation of inflammatory responses in glioma. J Mol Med (Berl). 2012;90(1):67–80. https://doi.org/10.1007/s00109-011-0807-6.
Soubannier V, Stifani S. NF-κB Signalling in Glioblastoma. Biomedicines. 2017;5(2). https://doi.org/10.3390/biomedicines5020029
Avci NG, Ebrahimzadeh-Pustchi S, Akay YM, et al. NF-κB inhibitor with Temozolomide results in significant apoptosis in glioblastoma via the NF-κB(p65) and actin cytoskeleton regulatory pathways. Scientific Reports. 2020/08/07 2020;10(1):13352. https://doi.org/10.1038/s41598-020-70392-5
Zhang Y, Liang X, Bao X, Xiao W, Chen G. Toll-like receptor 4 (TLR4) inhibitors: Current research and prospective. European Journal of Medicinal Chemistry. 2022/05/05/ 2022;235:114291. https://doi.org/10.1016/j.ejmech.2022.114291
Ramadass V, Vaiyapuri T, Tergaonkar V. Small Molecule NF-κB Pathway Inhibitors in Clinic. International journal of molecular sciences. 2020;21(14). https://doi.org/10.3390/ijms21145164
Patel MN, Carroll RG, Galván-Peña S, et al. Inflammasome Priming in Sterile Inflammatory Disease. Trends in Molecular Medicine. 2017/02/01/ 2017;23(2):165–180. https://doi.org/10.1016/j.molmed.2016.12.007
Pandey A, Shen C, Feng S, Man SM. Cell biology of inflammasome activation. Trends Cell Biol. 2021;31(11):924–39. https://doi.org/10.1016/j.tcb.2021.06.010.
Zahid A, Li B, Kombe AJK, Jin T, Tao J. Pharmacological Inhibitors of the NLRP3 Inflammasome. Mini Review. Frontiers in immunology. 2019-October-25 2019;10. https://doi.org/10.3389/fimmu.2019.02538
Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. The P2X7 Receptor-Interleukin-1 Liaison. Front Pharmacol. 2017;8:123. https://doi.org/10.3389/fphar.2017.00123.
Li G, Wang Z, Zhang C, et al. Molecular and clinical characterization of TIM-3 in glioma through 1,024 samples. Oncoimmunology. 2017;6(8):e1328339. https://doi.org/10.1080/2162402x.2017.1328339
Protti MP, De Monte L. Dual Role of Inflammasome Adaptor ASC in Cancer. Mini Review. Frontiers in Cell and Developmental Biology. 2020-February-04 2020;8. https://doi.org/10.3389/fcell.2020.00040
Li D, Hu W, Lin X, et al. CARD-Associated Risk Score Features the Immune Landscape and Predicts the Responsiveness to Anti-PD-1 Therapy in IDH Wild-Type Gliomas. Original Research. Frontiers in Cell and Developmental Biology. 2021-March-19 2021;9. https://doi.org/10.3389/fcell.2021.653240
Cvetkovic RS, Keating G. Anakinra. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2002;16(4):303–11; discussion 313–4. https://doi.org/10.2165/00063030-200216040-00005
Hübner M, Effinger D, Wu T, et al. The IL-1 Antagonist Anakinra Attenuates Glioblastoma Aggressiveness by Dampening Tumor-Associated Inflammation. Cancers (Basel). 2020;12(2). https://doi.org/10.3390/cancers12020433
Liu J, Gao L, Zhu X, et al. Gasdermin D Is a Novel Prognostic Biomarker and Relates to TMZ Response in Glioblastoma. Cancers (Basel). 2021;13(22). https://doi.org/10.3390/cancers13225620
Reilly M, Miller RM, Thomson MH, et al. Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating Phase I, Healthy Subjects Study of Intravenous OPN-305, a Humanized Anti-TLR2 Antibody. Clin Pharmacol Ther. 2013;94(5):593–600. https://doi.org/10.1038/clpt.2013.150.
Ziegler G, Freyer D, Harhausen D, Khojasteh U, Nietfeld W, Trendelenburg G. Blocking TLR2 in vivo Protects against Accumulation of Inflammatory Cells and Neuronal Injury in Experimental Stroke. J Cereb Blood Flow Metab. 2011;31(2):757–66. https://doi.org/10.1038/jcbfm.2010.161.
Dasu MR, Riosvelasco AC, Jialal I. Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis. 2009/01/01/ 2009;202(1):76–83. https://doi.org/10.1016/j.atherosclerosis.2008.04.010
Matsunaga N, Tsuchimori N, Matsumoto T, Ii M. TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules. Mol Pharmacol. 2011;79(1):34. https://doi.org/10.1124/mol.110.068064.
Yang J, Jiang H, Yang J, et al. Valsartan preconditioning protects against myocardial ischemia–reperfusion injury through TLR4/NF-κB signaling pathway. Molecular and Cellular Biochemistry. 2009/04/16 2009;330(1):39. https://doi.org/10.1007/s11010-009-0098-1
Gao W, Xiong Y, Li Q, Yang H. Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics. Review. Frontiers in Physiology. 2017-July-19 2017;8. https://doi.org/10.3389/fphys.2017.00508
Fang D, Yang S, Quan W, Jia H, Quan Z, Qu Z. Atorvastatin suppresses Toll-like receptor 4 expression and NF-κB activation in rabbit atherosclerotic plaques. Eur Rev Med Pharmacol Sci. 2014;18(2):242–6.
Monnet E, Shang L, Lapeyre G, et al. AB0451 NI-0101, a Monoclonal Antibody Targeting Toll Like Receptor 4 (TLR4) Being Developed for Rheumatoid Arthritis (RA) Treatment with a Potential for Personalized Medicine. Ann Rheum Dis. 2015;74(Suppl 2):1046–1046. https://doi.org/10.1136/annrheumdis-2015-eular.3801.
Loiarro M, Capolunghi F, Fantò N, et al. Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. J Leukoc Biol. 2007;82(4):801–10. https://doi.org/10.1189/jlb.1206746.
Sohma I, Fujiwara Y, Sugita Y, et al. Parthenolide, an NF-κB inhibitor, suppresses tumor growth and enhances response to chemotherapy in gastric cancer. Cancer Genomics Proteomics. 2011;8(1):39–47.
Zhang QQ, Ding Y, Lei Y, et al. Andrographolide suppress tumor growth by inhibiting TLR4/NF-κB signaling activation in insulinoma. Int J Biol Sci. 2014;10(4):404–14. https://doi.org/10.7150/ijbs.7723.
Xu S, Li X, Liu Y, Xia Y, Chang R, Zhang C. Inflammasome inhibitors: promising therapeutic approaches against cancer. J Hematol Oncol. 2019/06/26 2019;12(1):64. https://doi.org/10.1186/s13045-019-0755-0
Huang M, Zhang X, Toh GA, et al. Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature. 2021/04/01 2021;592(7856):773–777. https://doi.org/10.1038/s41586-021-03320-w
Hernandez P, Kim D, Haczku A. The Flying Monkeys of Ozone: Oxysterols Inactivate NLRP2 in Airway Epithelial Cells. Am J Respir Cell Mol Biol. 2021;65(5):461–3. https://doi.org/10.1165/rcmb.2021-0275ED.
Lamkanfi M, Mueller JL, Vitari AC, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol. 2009;187(1):61–70. https://doi.org/10.1083/jcb.200903124.
Kuwar R, Rolfe A, Di L, et al. A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury. J Neuroinflammation. 2019/04/11 2019;16(1):81. https://doi.org/10.1186/s12974-019-1471-y
Juliana C, Fernandes-Alnemri T, Wu J, et al. Anti-inflammatory Compounds Parthenolide and Bay 11–7082 Are Direct Inhibitors of the Inflammasome*. J Biol Chem. 2010/03/26/ 2010;285(13):9792–9802. https://doi.org/10.1074/jbc.M109.082305
Jiao J, Zhao G, Wang Y, Ren P, Wu M. MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury. Original Research. Frontiers in Molecular Biosciences. 2020-March-03 2020;7. https://doi.org/10.3389/fmolb.2020.00037
Jiang H, He H, Chen Y, et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 2017;214(11):3219–38. https://doi.org/10.1084/jem.20171419.
Marchetti C, Swartzwelter B, Koenders M, Dinarello C, Joosten L. OP0090 The human safe NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of experimental arthritis. Ann Rheum Dis. 2017;76(Suppl 2):89–89. https://doi.org/10.1136/annrheumdis-2017-eular.2775.
He H, Jiang H, Chen Y, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nature Communications. 2018/06/29 2018;9(1):2550. https://doi.org/10.1038/s41467-018-04947-6
Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263–9. https://doi.org/10.1038/nm.3804.
Yu S-X, Du C-T, Chen W, et al. Genipin inhibits NLRP3 and NLRC4 inflammasome activation via autophagy suppression. Scientific reports. 2015;5:17935. https://doi.org/10.1038/srep17935. http://europepmc.org/abstract/MED/26659006, https://europepmc.org/articles/PMC4675967, https://europepmc.org/articles/PMC4675967?pdf=render. Accessed 2015/12.
Guo Y, Li L, Xu T, et al. HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection. J Clin Invest. 12/01/ 2020;130(12):6301–6316. https://doi.org/10.1172/JCI138234
Sebastian-Valverde M, Wu H, Al Rahim M, et al. Discovery and characterization of small-molecule inhibitors of NLRP3 and NLRC4 inflammasomes. J Biol Chem. 2021;296. https://doi.org/10.1016/j.jbc.2021.100597
Li Q, Hua X, Li L, et al. AIP1 suppresses neovascularization by inhibiting the NOX4-induced NLRP3/NLRP6 imbalance in a murine corneal alkali burn model. Cell Communication and Signaling. 2022/05/06 2022;20(1):59. https://doi.org/10.1186/s12964-022-00877-5
Sun Y, Zhang M, Chen CC, et al. Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology. 2013;144(7):1478–87, 1487.e1–8. https://doi.org/10.1053/j.gastro.2013.02.038
Shen M, Meng Ln. Peripheral blood miR‑372 as a biomarker for ulcerative colitis via direct targeting of NLRP12. Exp Ther Med. 2019/08/01 2019;18(2):1486–1492. https://doi.org/10.3892/etm.2019.7707
Wang P-H, Ye Z-W, Deng J-J, et al. Inhibition of AIM2 inflammasome activation by a novel transcript isoform of IFI16. EMBO reports. 2018;19(10):e45737. https://doi.org/10.15252/embr.201845737
Li D, Wu R, Guo W, et al. STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production. Cell Rep. 2019;29(5):1249-1260.e4. https://doi.org/10.1016/j.celrep.2019.09.069.
Dell’Oste V, Gatti D, Gugliesi F, et al. Innate Nuclear Sensor IFI16 Translocates into the Cytoplasm during the Early Stage of <i>In Vitro</i> Human Cytomegalovirus Infection and Is Entrapped in the Egressing Virions during the Late Stage. J Virol. 2014;88(12):6970–82. https://doi.org/10.1128/JVI.00384-14.
Soriano-Teruel PM, García-Laínez G, Marco-Salvador M, et al. Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases. Cell death & disease. 2021;12(12):1155. https://doi.org/10.1038/s41419-021-04420-1
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119–31. https://doi.org/10.1056/NEJMoa1707914.
Poreba M, Strózyk A, Salvesen GS, Drag M. Caspase substrates and inhibitors. Cold Spring Harbor perspectives in biology. 2013;5(8):a008680. https://doi.org/10.1101/cshperspect.a008680
Li H, Guo Z, Chen J, et al. Computational research of Belnacasan and new Caspase-1 inhibitor on cerebral ischemia reperfusion injury. Aging. 2022;14(4):1848–64. https://doi.org/10.18632/aging.203907.
Kim YM, Talanian RV, Li J, Billiar TR. Nitric oxide prevents IL-1beta and IFN-gamma-inducing factor (IL-18) release from macrophages by inhibiting caspase-1 (IL-1beta-converting enzyme). J Immunol (Baltimore, Md : 1950). 1998;161(8):4122–8.
Bian ZM, Elner SG, Elner VM. Dual involvement of caspase-4 in inflammatory and ER stress-induced apoptotic responses in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2009;50(12):6006–14. https://doi.org/10.1167/iovs.09-3628.
Kwon Y-J, Kim T-Y, Lee S-W, Park Y-B, Lee S-K, Park M-C. AB0112 Caspase-5 inhibitor suppresses pro-inflammatory gene expressions in fibroblast like synoviocytes from patients with rheumatoid arthritis. Ann Rheum Dis. 2013;72(Suppl 3):A819–A819. https://doi.org/10.1136/annrheumdis-2013-eular.2435.
Hu JJ, Liu X, Xia S, et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020;21(7):736–45. https://doi.org/10.1038/s41590-020-0669-6.
Rathkey JK, Zhao J, Liu Z, et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Science immunology. Aug 24 2018;3(26). https://doi.org/10.1126/sciimmunol.aat2738
Stock TC, Bloom BJ, Wei N, et al. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J Rheumatol. 2012;39(4):720–7. https://doi.org/10.3899/jrheum.110874.
Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discovery. 2012;11(8):633–52. https://doi.org/10.1038/nrd3800.
Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Reviews Drug Discovery. 2012/08/01 2012;11(8):633–652. https://doi.org/10.1038/nrd3800
Fenini G, Contassot E, French LE. Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases. Front Pharmacol. 2017;8:278. https://doi.org/10.3389/fphar.2017.00278.
Acknowledgements
The authors would like to thank Kyung Gi Cho (CHA University) and Seok-Gu Kang (Yonsei University) for helpful comments on drafts of this manuscript. The authors thank the National Research Foundation of Korea (NRF) grant (Grant number: NRF-2021R1F1A105780111 and NRF-2021R1C1C1007810) for research support. The authors do not have any competing financial interests to declare in relation to this work
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This work was supported by National Research Foundation of Korea (NRF) grand [Grant number: NRF-2021R1F1A105780111 and NRF-2021R1C1C1007810].
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Sim, J., Park, J., Moon, JS. et al. Dysregulation of inflammasome activation in glioma. Cell Commun Signal 21, 239 (2023). https://doi.org/10.1186/s12964-023-01255-5
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DOI: https://doi.org/10.1186/s12964-023-01255-5