1. Enhanced IL-36R signaling promotes barrier impairment and inflammation in skin and intestine.
- Author
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Hovhannisyan Z, Liu N, Khalil-Aguero S, Panea C, VanValkenburgh J, Zhang R, Lim WK, Bai Y, Fury W, Huang T, Garnova E, Fairhurst J, Kim J, Aryal S, Ajithdoss D, Oyejide A, Del Pilar Molina-Portela M, E H, Poueymirou W, Oristian NS, Brydges S, Liu X, Olson W, Yancopoulos G, Murphy AJ, Sleeman MA, and Haxhinasto S
- Subjects
- Animals, Biomarkers, Dermatitis pathology, Disease Models, Animal, Disease Susceptibility, Gastroenteritis pathology, Humans, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Mice, Skin metabolism, Skin pathology, Dermatitis etiology, Dermatitis metabolism, Gastroenteritis etiology, Gastroenteritis metabolism, Receptors, Interleukin-1 metabolism, Signal Transduction
- Abstract
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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
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