IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis
| Autor: | Siew Eng Choon, Jonathan Barker, Marika Catapano, Francesca Capon, Satveer K. Mahil, Marco Romano, Marta Vergnano, Francesca D. Ciccarelli, Catherine H. Smith, Helen S. Young, Ian M. Carr, Helen J. Lachmann, Giovanna Lombardi, A. David Burden |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
FDR false discovery rate Neutrophils medicine.medical_treatment Gene Expression Inflammation Dermatology Plasmacytoid dendritic cell Disease Biochemistry Article pDC plasmacytoid dendritic cell 03 medical and health sciences 0302 clinical medicine Immune system Downregulation and upregulation Psoriasis medicine Humans PV psoriasis vulgaris CpG CpG-containing DNA Molecular Biology Computational & Systems Biology CAPS cryopyrin associated periodic syndrome business.industry Genome Integrity & Repair Dendritic Cells Cell Biology medicine.disease 030104 developmental biology Cytokine Gene Expression Regulation GPP generalized pustular psoriasis 030220 oncology & carcinogenesis Immunology TLR- 9 toll-like receptor 9 Generalized pustular psoriasis RNA Interferons medicine.symptom business Genetics & Genomics IL36R IL-36 receptor Interleukin-1 Signal Transduction |
| Zdroj: | 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 & Capon, F 2020, ' IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis ', Journal of Investigative Dermatology, vol. 140, no. 4, pp. 816-826.e3 . https://doi.org/10.1016/j.jid.2019.08.444 Catapano, M, Vergnano, M, Romano, M, Mahil, S K, Choon, S, Burden, A D, Young, H S, Carr, I M, Lachmann, H J, Lombardi, G, Smith, C H, Ciccarelli, F D, Barker, J N & Capon, F 2019, ' IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis ', Journal of Investigative Dermatology . https://doi.org/10.1016/j.jid.2019.08.444 The Journal of Investigative Dermatology |
| ISSN: | 0022-202X |
| DOI: | 10.1016/j.jid.2019.08.444 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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