GSE161406
Enhanced IL-36R signaling promotes barrier impairment and inflammation in skin and intestine
Deficiency in IL-36R antagonist caused by loss of function mutations in IL-36RN leads to DITRA (1), a rare inflammatory human disease that belongs to a subgroup of Generalized Pustular Psoriasis (GPP). Herein, we report a novel functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to one observed in DITRA patients which supports and provides new insight in our understanding of IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated IMQ-induced skin pathology at 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 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. Thus, our results indicate a central role for IL-36 in regulating the pro-inflammatory responses in the skin and epithelial barrier function in the intestine suggesting a new therapeutic potential for IL-36R axis in psoriasis and at the later stages of intestinal pathology. Overall design: RNA-seq of skin of IMQ-treated DITRA-like mice injected with PBS, anti-human IL-36R and anti-mouse IL-12p40 mAbs. RNA-seq of colon of DSS-treated DITRA-like mice injected with PBS, anti-human IL-36R and anti-mouse IL-12p40 mAbs.