IL-36 promotes systemic IFN-I responses in severe forms of psoriasis

Catapano, M. et al. (2020) IL-36 promotes systemic IFN-I responses in severe forms of psoriasis. Journal of Investigative Dermatology, 140(4), 816-826.e3. (doi: 10.1016/j.jid.2019.08.444) (PMID:31539532) (PMCID:PMC7097848)

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Abstract

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.

Item Type:Articles
Additional Information:The APRICOT clinical trial is funded by the Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership (grant EME 13/50/17 to CHS, FC, and JNB). MC is supported by the Psoriasis Association, MV by the UK Medical Research Council and
Keywords:Generalized pustular psoriasis, IL-36, PLSCR1, Type-I IFN, psoriasis vulgaris, systemic inflammation
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burden, Professor David
Authors: Catapano, M., Vergnano, M., Romano, M., Mahil, S. K., Choon, S.-E., Burden, A. D., Young, H. S., Carr, I. M., Lachmann, H. J., Lombardi, G., Smith, C. H., Ciccarelli, F. D., Barker, J. N., and Capon, F.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Investigative Dermatology
Publisher:Elsevier
ISSN:0022-202X
ISSN (Online):1523-1747
Published Online:17 September 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Journal of Investigative Dermatology 140(4): 816-826.e3
Publisher Policy:Reproduced under a Creative Commons License

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