IL-36 promotes systemic IFN-I responses in severe forms of psoriasis. CatapanoMarika VergnanoMarta RomanoMarco MahilSatveer K ChoonSiew-Eng BurdenA David YoungHelen S CarrIan M LachmannHelen J LombardiGiovanna SmithCatherine H CiccarelliFrancesca D BarkerJonathan N CaponFrancesca 2020 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.