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IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

Catapano, M; Vergnano, M; Romano, M; Mahil, SK; Choon, S-E; Burden, AD; Young, HS; ... Capon, F; + view all (2020) IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis. Journal of Investigative Dermatology , 140 (4) 816-826.e3. 10.1016/j.jid.2019.08.444. Green open access

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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.

Type: Article
Title: IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jid.2019.08.444
Publisher version: https://doi.org/10.1016/j.jid.2019.08.444
Language: English
Additional information: © 2019 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is 816 an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10101870
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