The IL17REL gene encodes a decoy receptor of IL-17 family cytokines to control gut inflammation.

Abstract

The IL17REL gene locus has been associated with susceptibility to inflammatory bowel disease (IBD). However, whether it encodes a functional protein and whether its IBD risk variants causally contribute to disease pathogenesis remain unknown. Here, we demonstrated that IL17REL encodes a decoy receptor capable of binding interleukin-17 (IL-17) family cytokines and suppressing intestinal inflammation. By contrast, proteins encoded by IBD-associated IL17REL variants lacked this function. We also showed that TGFβ1 induced IL17REL transcription, and its expression positively correlated with TGFB1 levels in IBD. Mechanistically, the IL-17REL protein competed with IL-17RA for IL-17A binding, an ability that is lost in the mutant form. Knock-in of IL17REL in mice alleviated 2,4,6-trinitrobenzene sulfonic acid-induced colitis, whereas knock-in of an IBD-associated IL17REL mutant did not. In addition, therapeutic administration of IL-17REL protein alleviated colitis symptoms. Together, these findings implicate IL-17REL variants in the pathogenesis of IBD and highlight IL-17REL as a potential therapeutic target.