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

Publication date: Available online 31 December 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Andrew Johnston, Xianying Xing, Liza Wolterink, Drew H. Barnes, ZhiQiang Yin, Laura Reingold, J. Michelle Kahlenberg, Paul W. Harms, Johann E. Gudjonsson
BackgroundGeneralized 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.ObjectiveTo understand better the disease mechanism of GPP to allow improved targeted therapies.MethodsWe 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.ResultsCompared 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.ConclusionsOur 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.

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Teaser

Current treatments for generalized pustular psoriasis are unsatisfactory. We applied recently-developed techniques for transcriptomic analysis of archived FFPE biopsies revealing pro-inflammatory IL-1, IL-17, TNF and IL-36 activity, which provides a rationale for biologic targeting of these cytokines.


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