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

• Published in: Science immunology 2020-12, Vol.5 (54)
• Main Authors: Hovhannisyan, Zaruhi, Liu, Nengyin, Khalil-Aguero, Sara, Panea, Casandra, VanValkenburgh, Jeffrey, Zhang, Ruoyu, Lim, Wei Keat, Bai, Yu, Fury, Wen, Huang, Tammy, Garnova, Elena, Fairhurst, Jeanette, Kim, Jee, Aryal, Smita, Ajithdoss, Dharani, Oyejide, Adelekan, Del Pilar Molina-Portela, Maria, E, Hock, Poueymirou, William, Oristian, Nicole Stokes, Brydges, Susannah, Liu, Xia, Olson, William, Yancopoulos, George, Murphy, Andrew J, Sleeman, Matthew A, Haxhinasto, Sokol
• Format: Article
• Language: English
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.aax1686

Deficiency in interleukin-36R (IL-36R) antagonist caused by loss-of-function mutations in 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.