SIGIRR Negatively Regulates IL-36-Driven Psoriasiform Inflammation and Neutrophil Infiltration in the Skin.

Autor:	Giannoudaki E; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Stefanska AM; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Lawler H; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Leon G; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Hernandez Santana YE; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Hassan N; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Russell SE; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Horan R; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Sweeney C; School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland., Preston RS; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland., Mantovani A; Scientific Institute for Research, Hospitalization and Healthcare, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; and.; The William Harvey Research Institute, Queen Mary University, London, United Kingdom., Garlanda C; Scientific Institute for Research, Hospitalization and Healthcare, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; and., Fallon PG; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland., Walsh PT; Trinity Translational Medicine Institute, School of Medicine, Trinity College, Dublin, Ireland; walshp10@tcd.ie.; National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2021 Jul 15; Vol. 207 (2), pp. 651-660. Date of Electronic Publication: 2021 Jul 12.
DOI:	10.4049/jimmunol.2100237
Abstrakt:	SIGIRR has been described as a negative regulator of several IL-1R/TLR family members and has been implicated in several inflammatory disease conditions. However, it is unknown whether it can suppress IL-36 family cytokines, which are members of the broader IL-1 superfamily that have emerged as critical orchestrators of psoriatic inflammation in both humans and mice. In this study, we demonstrate that SIGIRR is downregulated in psoriatic lesions in humans and mice, and this correlates with increased expression of IL-36 family cytokines. Using Sigirr -/- mice, we identify, for the first time (to our knowledge), SIGIRR as a negative regulator of IL-36 responses in the skin. Mechanistically, we identify dendritic cells and keratinocytes as the primary cell subsets in which IL-36 proinflammatory responses are regulated by SIGIRR. Both cell types displayed elevated IL-36 responsiveness in absence of SIGIRR activity, characterized by enhanced expression of neutrophil chemoattractants, leading to increased neutrophil infiltration to the inflamed skin. Blockade of IL-36R signaling ameliorated exacerbated psoriasiform inflammation in Sigirr -/- mice and inhibited neutrophil infiltration. These data identify SIGIRR activity as an important regulatory node in suppressing IL-36-dependent psoriatic inflammation in humans and mice. (Copyright © 2021 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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