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

TY - JOUR

T1 - IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

AU - Catapano, Marika

AU - Vergnano, Marta

AU - Romano, Marco

AU - Mahil, Satveer K.

AU - Choon, Siew-Eng

AU - Burden, A. David

AU - Young, Helen S.

AU - Carr, Ian M.

AU - Lachmann, Helen J

AU - Lombardi, Giovanna

AU - Smith, Catherine H.

AU - Ciccarelli, Francesca D.

AU - Barker, Jonathan N.

AU - Capon, Francesca

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85074495907&partnerID=8YFLogxK

U2 - 10.1016/j.jid.2019.08.444

DO - 10.1016/j.jid.2019.08.444

M3 - Article

C2 - 31539532

SN - 0022-202X

VL - 140

SP - 816-826.e3

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 4

ER -