Fig. 1
From: Generalized Pustular Psoriasis: A Review on Clinical Characteristics, Diagnosis, and Treatment
Adapted from Iznardo et al. [26]
Schematic representation of the signal transduction pathway activated by cytokines and genes involved in IL-36 autocrine and autoinflammatory circuits. The pathogenesis of GPP is related to mutations in multiple genes, such as the human IL-1Ra gene (IL1RN), IL-36Ra (IL36RN), caspase recruitment domain-containing protein 14 (CARD14), adapter protein complex 1 subunit sigma 3 (AP1S3), TNFAIP3-interacting protein 1 (TNIP1), and the gene coding for alpha-1 antichymotrypsin, also known as serine protease inhibitor gene serpin family A member 3 (SERPINA3). IL-1, TNF, and IL-17A promote the expression of IL-36 by keratinocytes. IL-36 cytokines are released as precursors requiring enzymatical cleavage by neutrophil-derived proteases (elastase, cathepsin G, or protease 3) and keratinocyte-derived cathepsin S. Mature IL-36 cytokines have 500-fold greater biological activity than their precursors and bind to IL-36R on the keratinocyte cell surface, acting in an autocrine manner to further induce IL-36 expression. In addition, they induce the production and secretion of neutrophil chemokines CXCL1, CXCL2, CXCL6, and CXCL8 (IL-8), increasing the attraction of neutrophils to the skin. Serine protease inhibitors such as alpha-1 antitrypsin or alpha-1 antichymotrypsin (encoded by SERPINA1 and SERPINA3, respectively) can inhibit neutrophil proteases.