# Generalized Pustular Psoriasis and Systemic Organ Dysfunctions
## 3 The Pathogenesis of GPP  
The interleukin-36 (IL-36) pathway plays a critical role in GPP [42; 43], as evidenced by loss-of-function mutations in the IL36 RN gene and related genes such as CARD14, AP1S3, SERPINA3, and MPO, and the overexpression of IL-36 cytokines in GPP lesions [44; 45; 46; 47] (Figure 1). Consistently, clinical improvements have been observed with spesolimab, an anti-IL-36 receptor antibody, indicating a therapeutic potential for targeting this pathway [48]. The pathogenesis of GPP is complex and likely involves both genetic and environmental factors. Significant ongoing research efforts are being made to understand the mechanisms underlying both non-pustular and pustular psoriasis, with some mechanistic overlaps, particularly in patients presenting with both GPP and psoriasis vulgaris (PV) [49; 50]. GPP can present independently with unique clinical and histological features, differing in age of onset and sex distribution compared to PV, suggesting distinct underlying mechanisms. The immunogenic nature of psoriasis involves an interplay between the innate and adaptive immune systems. In PV, T-cell-derived cytokines like IL-17 are therapeutically targeted with high efficacy [51; 52; 53; 54]. In contrast, GPP involves \"autoinflammatory\" responses triggered by innate immune alterations [55; 56]. Neutrophils, crucial in innate immunity, play a significant role in GPP by contributing to oxidative stress, degranulation, and forming neutrophil extracellular traps (NETs) [57]. The IL-36 cytokines, part of the IL-1 family, are activated extracellularly through proteolytic cleavage by neutrophil- and keratinocyte-derived proteases, unlike the classic IL-1 cytokines that are activated intracellularly [58; 59; 60]. Activation of IL-36 involves several proteases, with specific cytokines activated by distinct proteases [61; 62; 63]. The IL-36 signaling pathway is crucial for activating downstream MYD88-mediated pathways such as NF-kB and MAPK [64; 65; 66]. Negative regulators like SERPINA1 and SERPINA3 modulate this activity, suggesting complex regulation of inflammation in GPP [67; 68]. IL-36 cytokines, including IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\), play crucial roles in regulating immune functions, primarily through the upregulation of several key molecules. These cytokines facilitate robust immune responses by increasing the production of IL-6 and other pro-inflammatory cytokines and chemokines from bone marrow-derived dendritic cells (BMDCs) [69]. They also enhance the expressions of CD80, CD86, and MHC class II on these cells, which improve the ability to present antigens and activate T cells [62]. Furthermore, IL-36\(\gamma\) specifically upregulates ICAM-1 and VCAM-1 on endothelial cells, which aids in monocyte adhesion and promotes chemokine production in human dermal microvascular endothelial cells (HDMEC) [70]. Additionally, IL-36 enhances IFNy secretion in response to anti-CD3 stimulation in splenocytes and boosts its production in CD4\({}^{+}\) T cells [62]. In murine studies, IL-36\(\alpha\)-treated dendritic cells show increased expressions of CD40, CD80, and CD86, leading to enhanced CD4+ T cell proliferation. These cells also induce Rorc expression and IL-17A production in ovalbumin-specific CD4+ T cells. Moreover, IL-36 enhances the production of IL-16, IL-6, and IL-23, which promote Th17 differentiation [70]. Figure 1: The pathogenesis of GPP. The interleukin-36 (IL-36) pathway is key in generalized pustular psoriasis (GPP), marked by genetic mutations and high levels of IL-36 proteins in GPP lesions. GPP triggers “autoinflammatory” responses through changes in the innate immune system. Neutrophils, a core part of this system, contribute to inflammation by causing oxidative stress, releasing enzymes, and forming neutrophil extracellular traps (NETs). IL-36 cytokines, belonging to the IL-1 family, are uniquely activated outside of cells by proteases from neutrophils and keratinocytes.