Synbindin 可抑制结肠炎期间微生物群和黏膜炎症相关的促炎巨噬细胞活化。
Synbindin restrains proinflammatory macrophage activation against microbiota and mucosal inflammation during colitis.
机构信息
State 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
State 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.
出版信息
Gut. 2021 Dec;70(12):2261-2272. doi: 10.1136/gutjnl-2020-321094. Epub 2021 Jan 13.
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 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 . 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.
目的
作为一种规范的膜连接因子，synbindin 的功能不断扩展，并在免疫反应中得到了体现。在这里，我们研究了 synbindin 在调节结肠炎期间 TLR4 信号和巨噬细胞对微生物群的反应中的作用。
设计
构建了三种不同的小鼠模型，允许 synbindin 进行全局、髓系特异性或肠上皮细胞特异性杂合缺失，以揭示 synbindin 在葡聚糖硫酸钠（DSS）结肠炎期间的功能。评估了 synbindin 对 TLR4 信号和巨噬细胞对细菌脂多糖（LPS）或 的激活的影响。通过免疫荧光和共免疫沉淀确定 synbindin 与 Rab7b 的共定位和相互作用。检测了活性 IBD 患者循环单核细胞和肠黏膜巨噬细胞中的 synbindin 表达。
结果
全局 synbindin 杂合不足极大地加剧了 DSS 诱导的肠道炎症。肠道微生物群耗竭消除了对 DSS 的易感性，而在髓系细胞而非肠上皮细胞中特异性 synbindin 杂合缺失则模拟了这种情况。在 synbindin 干扰后，巨噬细胞中观察到明显异常的促炎基因特征和过度的 TLR4 信号。在 DSS 结肠炎小鼠和活动 IBD 患者的肠黏膜巨噬细胞和循环单核细胞中，synbindin 显著增加。白细胞介素 23 和粒细胞-巨噬细胞集落刺激因子被鉴定为诱导 synbindin 表达。机制特征表明，synbindin 与 Rab7b 共定位并直接相互作用，Rab7b 协调 TLR4 的内体降解途径以终止信号。
结论
Synbindin 是 TLR4 信号的关键调节剂，可在结肠炎期间抑制针对微生物群的促炎巨噬细胞激活。
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