# New and Emerging Treatments for Generalized Pustular Psoriasis: Focus on IL-36 Receptor Inhibitors
## 3 Pathophysiology of GPP  
Currently, the understanding of the pathophysiological mechanisms of GPP remains incomplete. According to the European Rare and Severe Psoriasis Expert Network (ERASPEN) definition, although GPP shares substantial cytokine pathway overlap with plaque psoriasis, its genetics and pathophysiology diverge significantly [10; 11; 12]. Plaque psoriasis is an autoimmune condition, involving both innate and adaptive immunopathogenic responses. In contrast, GPP is an autoimmunity condition, resulting primarily from an innate immune inflammation [12]. Some experts even consider it an example of an autoimmunity keratinization disease [13]. Its histopathology is characterized by the epidermal infiltration of neutrophils and mononuclear cells, leading to the formation of clinically evident, sterile pustules [14]. Current scientific evidence supports that the IL-36 axis plays a fundamental role in the innate immune system hyperactivation observed in GPP [15]. IL-36 cytokines are part of the IL-1 superfamily and consist of three pro-inflammatory agonists (IL-36\(\alpha\), IL-36\(\beta\), IL-36\(\gamma\)and the IL-36 receptor antagonist. These cytokines are expressed by various cell types, including keratinocytes, epithelial cells, and immune cells, and they act upon these cells in both an autocrine and paracrine fashion [12; 15]. They are released as precursors and, to become bioactive, they need to be proteolytically cleaved by specific proteases, particularly neutrophil-derived proteases [15; 16]. The three proinflammatory agonists activate nuclear factor-kB (NF-kB) and mitogen-activated protein kinase by binding to the IL-36 receptor (IL-36R). Consequently, downstream pathways are triggered, leading to the production of pro-inflammatory cytokines, chemokines, and co-stimulatory molecules. This process is usually regulated by IL-36 Ra, a cytokine that competes with IL-36 agonists for binding to IL-36R, thereby preventing the activation of these pathways (Figure 1) [15]. When IL-36 agonists are excessively expressed or when the function of IL-36 Ra is impaired, it triggers a positive feedback loop, leading to uncontrolled signaling and the overproduction of inflammatory cytokines. As a result, chemokines such as CXCL1 and CXCL8, known for their pro-inflammatory properties, are induced. This creates a chemokine gradient that attracts numerous neutrophils to the epidermis, leading to the development of  
Figure 1: The IL-36 signaling pathway. Keratinocytes secrete IL-36 cytokines as precursors. These are cleaved, becoming biologically active, and bind to IL-36 on the surface of keratinocytes, inducing an inflammatory cascade that promotes IL-36 expression. IL-36 cytokines also induce the expression of numerous cytokines, neutrophil chemokines, and lymphokines, further propagating this pro-inflammatory cycle. _AP-1_-activating protein-1, _CARD_ caspase recruitment domain, _CCL_ chemokine (C–C motif) ligand, _CXCL_ chemokine (C–X–C motif) ligand, _IL_ interleukin, _MAPK_ mitogen-activated protein kinase, _mRNA_ messenger RNA, _NET_ neutrophil extracellular trap, _NFkB_ nuclear factor kappa-light-chain-enhancer of activated B cells, _R receptor_ RA receptor antagonist, _RACP_ receptor accessory protein, and _TNF_ tumor necrosis factor. Image retrieved from [PERSON] et al. 2022 [12]. Licensed under a Creative Commons Attribution-Non-commercial 4.0 International License. License statement: this image is licensed under a Creative Commons Attribution-Non-commercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as appropriate credit is given to the original author(s) and the source, and a link to the Creative Commons license is provided. To view a copy of this license, visit [[http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/)]([http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/)) (accessed on 31 May 2024).