Title : Gut mucosal immunity and inflammatory bowel disease
Abstract:
The mammalian gut harbors trillions of commensal bacteria that interact with their hosts through various bioactive molecules. However, the mutualistic strategies that hosts evolve to benefit from these symbiotic relationships are largely unexplored. Here we report that mouse enterocytes secrete apolipoprotein L 9a/b (APOL9a/b) in the presence of microbiota. By integrating flow-cytometry sorting of APOL9-binding bacterial taxa with 16S rRNA gene sequencing (APOL9-seq), we identify that APOL9a/b, as well as their human equivalent APOL2, coat gut bacteria belonging to the order of Bacteroidales with a high degree of specificity through commensal ceramide-1-phosphate (Cer1P) lipids. Genetic abolition of Cer1P synthesis pathways in gut-dominant symbiote Bacteroides thetaiotaomicron significantly decreases the binding of APOL9a/b to the bacterium. Instead of lysing the bacterial cells, coating of APOL9a/b induces the production of outer membrane vesicles (OMVs) from the target bacteria. Subsequently, the Bacteroides-elicited OMVs enhance the host's interferon-gamma (IFNγ) signaling to promote MHC class II (MHC-II) expression in the intestinal epithelial cells (IECs). In mice, the loss of Apol9a/b compromises the gut MHC-II-instructed immune barrier function, leading to early mortality from infection by intestinal pathogens. Our data reveal how a host-elicited factor benefits gut immunological homeostasis by selectively targeting commensal ceramide molecules.
Dysreuption of gut immune homeostasis results in inflammatory bowel disease. Th17-derived IL-17A, also known simply as IL-17, is a key pro-inflammatory cytokine that synergizes with TNF to amplify inflammatory responses. 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. 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 demonstrate that IL17REL encodes 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, the protein encoded by IBD-associated IL17REL variants lacks this function. IL-17REL is highly expressed in gut immune cells and its expression levels are increased in IBD samples. TGF-β1 induces IL17REL transcription through SMAD2/3 binding site, and its expression positively correlates with TGFB1 levels in IBD. Mechanistically, IL-17REL protein is released out of cells by ATP, and competes with IL-17RA for IL-17A binding, an ability that is lost in the mutant form. Consequently, IL-17REL suppresses IL-17A-mediated inflammatory gene expression. Knock-in of IL17REL in mice alleviates TNBS-induced colitis, whereas knock-in of an IBD-associated IL17REL mutant does not. In addition, therapeutic administration of IL-17REL protein alleviates colitis symptoms. Taken together, these findings implicate IL-17REL variants in the pathogenesis of IBD and highlight IL-17REL as a potential therapeutic target.
