Research ArticleCYTOKINES

Enhanced IL-36R signaling promotes barrier impairment and inflammation in skin and intestine

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Science Immunology  18 Dec 2020:
Vol. 5, Issue 54, eaax1686
DOI: 10.1126/sciimmunol.aax1686

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Sequelae of unrestrained IL-36 signaling

The IL-36 receptor integrates signals from three proinflammatory IL-36 agonist ligands opposed by one natural antagonist (IL-36Ra). Hovhannisyan et al. developed mice humanized for the extracellular portion of IL-36R and the IL-36 agonists (α, β, and γ) to evaluate anti-inflammatory treatment using antibodies blocking the human IL-36R. The mouse version of IL-36Ra retained by these mice is a weaker inhibitor at the human IL-36R than its human counterpart, leaving these mice susceptible to enhanced skin and intestinal inflammation after epithelial barrier insults. Antibodies blocking the IL-36R or the shared p40 subunit of IL-12/IL-23 interrupted an overlapping set of proinflammatory circuits in these mice, indicating that IL-36R–targeting therapeutics are candidates to treat some of the same human diseases responsive to inhibition of the IL-23/IL-17 axis.

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