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.


Deficiency in interleukin-36R (IL-36R) antagonist caused by loss-of-function mutations in IL-36RN leads to DITRA (deficiency of IL-36 receptor antagonist), a rare inflammatory human disease that belongs to a subgroup of generalized pustular psoriasis (GPP). We report a functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to that observed in patients with DITRA, which provides new insight into our understanding of the IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in a preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated imiquimod-induced skin pathology as both prophylactic and therapeutic treatments. Deeper characterization of the humanized DITRA-like mice revealed that deregulated IL-36R signaling promoted tissue pathology during intestinal injury and led to impairment in mucosal restoration in the repair phase of chronic dextran sulfate sodium (DSS)–induced colitis. Blockade of IL-36R pathway significantly ameliorated DSS-induced intestinal inflammation and rescued the inability of DITRA-like mice to recover from mucosal damage in vivo. Our results indicate a central role for IL-36 in regulating proinflammatory responses in the skin and epithelial barrier function in the intestine, suggesting a new therapeutic potential for targeting the IL-36R axis in psoriasis and at the later stages of intestinal pathology in inflammatory bowel disease.

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