ECM1 is an essential factor for the determination of M1 macrophage polarization in IBD in response to LPS stimulation
ECM1 is an essential factor for the determination of M1 macrophage polarization in IBD in response to LPS stimulation
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ECM1 是确定 IBD 中 M1 巨噬细胞响应 LPS 刺激极化的重要因素
DOI：
10.1073/pnas.1912774117
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发表时间：
2020-02-11
影响因子：
11.1
通讯作者：
Sun, Bing
中科院分区：
文献类型：
--
作者：
Zhang, Yaguang;Li, Xuezhen;Sun, Bing
意义炎症性肠病(IBD)会使人虚弱，有时会导致危及生命的并发症。巨噬细胞通过分泌多种细胞因子，调节组织修复，在结肠炎发病中发挥重要作用。在这里，我们提供的证据表明，IBD易感基因ECM1在结肠炎中通过巨噬细胞控制结肠炎至关重要。巨噬细胞ECM1缺乏导致对葡聚糖硫酸钠诱导的结肠炎敏感性降低，粒细胞-巨噬细胞集落刺激因子(GM-CSF)促进的精氨酸酶1表达增加，并通过激活STAT5途径削弱M1极化。这些结果揭示了IBD易感基因ECM1通过GM-CSF/STAT5调节轴在结肠巨噬细胞中的作用，提示降低巨噬细胞ECM1功能是治疗IBD的一种潜在策略。炎症性肠病(IBD)是一种以肠道炎症和上皮损伤为主要病理特征的慢性复发性胃肠道疾病。在这里，我们揭示了细胞外基质蛋白1(ECM1)在促进人和小鼠IBD发病中的作用。ECM1在巨噬细胞，尤其是炎症条件下的组织浸润性巨噬细胞中高表达，在IBD进展过程中显著诱导表达。巨噬细胞特异性的ECM1基因敲除导致精氨酸酶1(ARG1)表达增加，并在脂多糖(LPS)处理后减弱向M1巨噬细胞表型的极化。机制研究表明，ECM1可通过粒细胞-巨噬细胞集落刺激因子/STAT5信号通路调节M1巨噬细胞极化。葡聚糖硫酸钠诱导的IBD小鼠的病理变化通过巨噬细胞中ECM1基因的特异性敲除而得到缓解。综上所述，我们的发现表明，ECM1在促进M1巨噬细胞极化方面具有重要作用，而M1巨噬细胞极化对于控制肠道炎症和组织修复至关重要。
Significance Inflammatory bowel disease (IBD) can be debilitating, and sometimes leads to life-threatening complications. Macrophages play a critical role in colitis by secreting many cytokines and regulating tissue repair. Here, we provide evidence showing that the IBD susceptibility gene ECM1 is critical for controlling colonic inflammation through macrophages in colitis. ECM1 deficiency in macrophages resulted in reduced sensitivity to dextran sodium sulphate-induced colitis with increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF)-promoted arginase 1 and impaired M1 polarization by activating the STAT5 pathway. These results reveal a function of the IBD susceptibility gene ECM1 in colonic macrophages through GM-CSF/STAT5 regulatory axis and indicate that the attenuation of ECM1 function in macrophages is a potential strategy for IBD therapy. Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the granulocyte-macrophage colony-stimulating factor/STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.