Title : The IL17REL gene encodes a decoy receptor of IL-17 family cytokines to control gut inflammation
Abstract:
IL-17 family comprises six cytokines (IL-17A to IL-17F) and five receptors (IL-17RA to IL-17RE). IL-17RA acts as a common receptor subunit for several cytokines of the family. IL-17A, also known simply as IL-17, is a key pro-inflammatory cytokine that synergizes with TNF to amplify inflammatory responses. Sequence similarity analysis from human genome project suggests that IL17REL encodes a member of the IL-17 receptor family. 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 encoded a decoy receptor capable of binding IL-17 family cytokines (IL-17A, IL-17C and IL-17F) and suppressing intestinal inflammation in TNBS colitis model. In contrast, proteins encoded by IBD-associated IL17REL variants lacked this function. We found that IL-17REL was highly expressed in gut immune cells and its expression levels were increased in IBD samples. We also showed that TGF-β1 induced IL17REL transcription through SMAD2/3 binding site, and its expression positively correlated with TGFB1 levels in IBD. Mechanistically, the IL-17REL protein was released out of cells by ATP, and competed with IL-17RA for IL-17A binding, an ability that was lost in the mutant form. Consequently, IL-17REL suppressed IL-17A-mediated inflammatory gene expression. Knock-in of IL17REL in mice alleviated TNBS-induced colitis, whereas knock-in of an IBD-associated IL17REL mutant did not. In addition, therapeutic administration of IL-17REL protein alleviated colitis symptoms. Taken together, these findings implicate IL-17REL variants in the pathogenesis of IBD and highlight IL-17REL as a potential therapeutic target.
