TY - JOUR T1 - Synbindin restrains proinflammatory macrophage activation against microbiota and mucosal inflammation during colitis JF - Gut JO - Gut SP - 2261 LP - 2272 DO - 10.1136/gutjnl-2020-321094 VL - 70 IS - 12 AU - Luoyan Ai AU - Yimeng Ren AU - Mingming Zhu AU - Shiyuan Lu AU - Yun Qian AU - Zhaofei Chen AU - Antao Xu Y1 - 2021/12/01 UR - http://gut.bmj.com/content/70/12/2261.abstract N2 - Objective As a canonical membrane tethering factor, the function of synbindin has been expanding and indicated in immune response. Here, we investigated the role of synbindin in the regulation of toll-like receptor 4 (TLR4) signalling and macrophage response to microbiota during colitis.Design Three distinct mouse models allowing global, myeloid-specific or intestinal epithelial cell-specific synbindin heterozygous deletion were constructed and applied to reveal the function of synbindin during dextran sodium sulfate (DSS) colitis. Effects of synbindin on TLR4 signalling and macrophage activation in response to bacterial lipopolysaccharide (LPS) or Fusobacterium nucleatum were evaluated. The colocalisation and interaction between synbindin and Rab7b were determined by immunofluorescence and coimmunoprecipitation. Synbindin expression in circulating monocytes and intestinal mucosal macrophages of patients with active IBD was detected.Results Global synbindin haploinsufficiency greatly exacerbated DSS-induced intestinal inflammation. The increased susceptibility to DSS was abolished by gut microbiota depletion, while phenocopied by specific synbindin heterozygous deletion in myeloid cells rather than intestinal epithelial cells. Profoundly aberrant proinflammatory gene signatures and excessive TLR4 signalling were observed in macrophages with synbindin interference in response to bacterial LPS or Fusobacterium nucleatum. Synbindin was significantly increased in intestinal mucosal macrophages and circulating monocytes from both mice with DSS colitis and patients with active IBD. Interleukin 23 and granulocyte-macrophage colony-stimulating factor were identified to induce synbindin expression. Mechanistic characterisation indicated that synbindin colocalised and directly interacted with Rab7b, which coordinated the endosomal degradation pathway of TLR4 for signalling termination.Conclusion Synbindin was a key regulator of TLR4 signalling and restrained the proinflammatory macrophage activation against microbiota during colitis.All data relevant to the study are included in the article or uploaded as supplementary information. ER -