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

Johnston, Andrew, PhD ; Xing, Xianying, PhD ; Wolterink, Liza, BS ; Barnes, Drew H., BS ; Yin, ZhiQiang, MD, PhD ; Reingold, Laura, BS ; Kahlenberg, J. Michelle, MD, PhD ; Harms, Paul W., MD, PhD ; Gudjonsson, Johann E., MD, PhD

Journal of allergy and clinical immunology, 2017-07, Vol.140 (1), p.109-120 [Peer Reviewed Journal]

United States: Elsevier Limited

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Title:
IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis
Author: Johnston, Andrew, PhD ; Xing, Xianying, PhD ; Wolterink, Liza, BS ; Barnes, Drew H., BS ; Yin, ZhiQiang, MD, PhD ; Reingold, Laura, BS ; Kahlenberg, J. Michelle, MD, PhD ; Harms, Paul W., MD, PhD ; Gudjonsson, Johann E., MD, PhD
Subjects: Allergy and Immunology ; Biopsy ; Cathepsin G ; Cell activation ; Cell culture ; Cells, Cultured ; Cytokines ; Cytokines - genetics ; Cytokines - immunology ; Disease ; Elastase ; Formaldehyde ; Gene expression ; Humans ; Immunohistochemistry ; Interferon ; Interleukin 1 ; Keratinocytes ; Keratinocytes - immunology ; Lesions ; Leukocytes (neutrophilic) ; Mutation ; Neutrophils ; Neutrophils - immunology ; Ontology ; Paraffin ; Pathogenesis ; Polymerase chain reaction ; Principal components analysis ; Protease inhibitors ; Proteinase inhibitors ; Psoriasis ; Psoriasis - immunology ; RNA, Messenger - metabolism ; Skin - cytology ; Skin - immunology ; Skin diseases ; Tumor necrosis factor
Is Part Of: Journal of allergy and clinical immunology, 2017-07, Vol.140 (1), p.109-120
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Description: 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 and warrant a better understanding of GPP pathogenesis. Objective We sought 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 quantitative RT-PCR and immunohistochemistry, and a potential disease mechanism was 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 IFN-γ mRNA expression than PV lesions did. We detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules, and we 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.
Publisher: United States: Elsevier Limited
Language: English

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

Johnston, Andrew, PhD ; Xing, Xianying, PhD ; Wolterink, Liza, BS ; Barnes, Drew H., BS ; Yin, ZhiQiang, MD, PhD ; Reingold, Laura, BS ; Kahlenberg, J. Michelle, MD, PhD ; Harms, Paul W., MD, PhD ; Gudjonsson, Johann E., MD, PhD

United States: Elsevier Limited

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