The Francis Crick Institute
1-s2.0-S0022202X19332324-main (4).pdf (1.11 MB)

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

Download (1.11 MB)
journal contribution
posted on 2020-04-17, 11:00 authored by Marika Catapano, Marta Vergnano, Marco Romano, Satveer K Mahil, Siew-Eng Choon, A David Burden, Helen S Young, Ian M Carr, Helen J Lachmann, Giovanna Lombardi, Catherine H Smith, Francesca D Ciccarelli, Jonathan N Barker, Francesca Capon
Psoriasis is an immune-mediated skin disorder associated with severe systemic co-morbidities. While 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 extra-cutaneous 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 generalised pustular psoriasis (GPP), a clinical variant associated with pervasive up-regulation of IL-36 signalling. By undertaking blood and neutrophil RNA-sequencing, we demonstrated that affected individuals display a prominent Type-I IFN signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 de-regulation and Type-I IFN over-expression in patients with severe psoriasis vulgaris (PsV). We also found that the activation of Type-I IFN genes was associated with extra-cutaneous morbidity, in both GPP and PsV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells (pDCs), where it potentiates Toll-like Receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the up-regulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/Type-I IFN axis contributing to extra-cutaneous inflammation in psoriasis.