IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

Abstract

Background Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory warranting a better understanding of GPP pathogenesis. Objective To understand better the disease mechanism of GPP to allow improved targeted therapies. Methods We performed a gene expression study on formalin-fixed paraffin-embedded GPP (n=28) and PV (n=12) lesional biopsies and healthy control (n=20) skin. Differential gene expression was analyzed using gene ontology and enrichment analysis. Gene expression was validated with qRT-PCR and immunohistochemistry, and a potential disease mechanism investigated using primary human cell culture. Results Compared with healthy skin, GPP lesions yielded 479 and PV 854 differentially expressed genes respectively, with 184 upregulated in both diseases. We detected significant contributions of IL-17A, TNF, IL-1, IL-36 and interferons in both diseases; although GPP lesions furnished higher IL-1 and IL-36 and lower IL-17A and interferon-γ mRNA expression than PV. We detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules and show that both neutrophils and neutrophil proteases activate IL-36. Suggesting another mechanism regulating IL-36 activity, the protease inhibitors serpin A1 and A3, which inhibit elastase and cathepsin G respectively, were upregulated in both diseases and inhibited activation of IL-36. Conclusions Our data indicate sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a potent driver of disease pathology in GPP.

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

“…2), most likely because of lack of N-terminal processing 35 . In agreement with previous findings 25,36 , IL-36 can be activated by proteases that are released by activated neutrophils, including elastase (Supplementary Fig. S7).…”

“…The expression of IL-36 cytokines is elevated in many inflammatory diseases 22,41 . In particular, high IL-36 as well as mutations in IL-36 signaling components The mean values ± SD of are associated with psoriasis 25,30,[42][43][44][45] . The findings that IL-17A induced the expression of the IL-36 cytokines suggested that these are downstream effectors of IL-17A.…”

“…As mentioned above, IL-36 cytokines require processing to gain biological activity [34][35][36] . IL-36 can be processed and activated by proteases derived from neutrophils 25,36 . Elastase, one of these proteases, was capable of activating DEFB4A, IL36G, and S100A7A gene expression in naïve NHEK monolayer cultures cooperatively with IL-17A-treated NHEK supernatants ( Fig.…”

“…Members of the IL-36 family, which are IL-1 type cytokines, have also been implicated in psoriasis 22,23 . IL-36 cytokines are involved in the crosstalk between immune cells and keratinocytes and thus are potentially participating in controling the proinflammatory milieu in psoriatic skin [24][25][26][27][28][29][30] . Moreover, interaction of IL-17 and IL-36 has been postulated to promote inflammation 26,31 .…”

“…α1-antitrypsin was not fully repressing the cooperative effects suggesting that these are not the only neutrophilic proteases involved. IL-36α and β are expressed in the NHEKs in response to IL-17A and might also contribute to the cooperative effects, particularly as they are activated by distinct proteases 25,36 . The importance of neutrophil-derived proteases was further demonstrated by the activation of latent IL-36γ in the presence of neutrophil supernatants or by elastase as measured by DEFB4A and S100A7A expression ( Supplementary Fig.…”