Synbindin restrains proinflammatory macrophage activation against microbiota and mucosal inflammation during colitis
Synbindin restrains proinflammatory macrophage activation against microbiota and mucosal inflammation during colitis
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Synbindin 抑制结肠炎期间微生物群和粘膜炎症的促炎巨噬细胞活化
DOI：
10.1136/gutjnl-2020-321094
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发表时间：
2021-12-01
期刊：
影响因子：
24.5
通讯作者：
Xu, Antao
中科院分区：
文献类型：
--
作者：
Ai, Luoyan;Ren, Yimeng;Xu, Antao
目的synbindin作为一种典型的膜结合因子，其功能正在不断扩展，并在免疫应答中发挥重要作用。在这里，我们研究了synbindin在结肠炎期间调节Toll样受体4（TLR 4）信号传导和巨噬细胞对微生物群的反应中的作用。设计三个不同的小鼠模型，允许全球，骨髓特异性或肠上皮细胞特异性synbindin杂合缺失的构建和应用，以揭示在葡聚糖硫酸钠（DSS）结肠炎synbindin的功能。评价了synbindin对响应于细菌脂多糖（LPS）或具核梭杆菌（Fusobacterium nucleatum）的TLR 4信号传导和巨噬细胞活化的影响。synbindin和Rab 7 b之间的共定位和相互作用通过免疫荧光和免疫共沉淀来确定。检测活动期IBD患者外周血单核细胞和肠粘膜巨噬细胞中Synbindin的表达。结果整体synbindin单倍型不足明显加重DSS诱导的肠道炎症反应。对DSS的敏感性增加被肠道微生物群消耗所消除，而表型被骨髓细胞而不是肠上皮细胞中的特异性synbindin杂合缺失所模仿。在巨噬细胞中观察到严重异常的促炎基因特征和过度的TLR 4信号传导，其中synbindin干扰对细菌LPS或具核梭杆菌的响应。Synbindin在DSS结肠炎小鼠和活动性IBD患者的肠粘膜巨噬细胞和循环单核细胞中显著增加。白细胞介素23和粒细胞-巨噬细胞集落刺激因子被确定为诱导synbindin表达。机制表征表明，synbindin共定位，并直接与Rab 7 b，协调TLR 4的信号传导终止的内体降解途径相互作用。结论Synbindin是TLR 4信号通路的关键调节因子，抑制结肠炎时巨噬细胞对微生物群的促炎性激活。
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.