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Original research
Synbindin restrains proinflammatory macrophage activation against microbiota and mucosal inflammation during colitis
  1. Luoyan Ai1,
  2. Yimeng Ren1,
  3. Mingming Zhu1,
  4. Shiyuan Lu1,
  5. Yun Qian1,
  6. Zhaofei Chen1,
  7. Antao Xu2
  1. 1State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  2. 2Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  1. Correspondence to Dr Luoyan Ai, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; storysparrow{at}; Dr Antao Xu, Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; antaoxu{at}


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.

  • ulcerative colitis
  • macrophages
  • colonic microflora
  • gut immunology

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  • LA, YR and MZ contributed equally.

  • Contributors LY Ai, YM Ren, MM Zhu, SY Lu, Y Qian, ZF Chen and AT Xu performed the experiments and analyzed data. LY Ai and AT Xu conceived and wrote the study. AT Xu designed or/and supervised this project and revised the study.

  • Funding This project was supported by grants from the National Natural Science Foundation of China: 81800485, 81600435 and 81772517.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study protocol was approved by the ethics committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University. All the research was carried out in accordance with the provisions of the Declaration of Helsinki of 1975.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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