Tim-3 promotes intestinal homeostasis in DSS colitis by inhibiting M1 polarization of macrophages
Tim-3 promotes intestinal homeostasis in DSS colitis by inhibiting M1 polarization of macrophages
复制标题
Tim-3 通过抑制巨噬细胞的 M1 极化来促进 DSS 结肠炎的肠道稳态。
DOI：
10.1016/j.clim.2015.07.008
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发表时间：
2015-10-01
影响因子：
8.6
通讯作者：
Han, Gencheng
中科院分区：
文献类型：
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作者：
Jiang, Xingwei;Yu, Jiahui;Han, Gencheng
Tim-3参与炎症性肠病（IBD）的病理生理学，但其潜在机制尚不清楚。在这里，我们证明，在患有DSS结肠炎的小鼠中，Tim-3抑制致病性促炎性M1巨噬细胞的极化，而Tim-3下调或阻断导致M1反应增加。Tim-3沉默的巨噬细胞的连续转移使DSS结肠炎恶化并增强炎症，而Tim-3过表达通过降低M1巨噬细胞反应来减弱DSS结肠炎。Tim-3过表达的巨噬细胞与肠淋巴细胞的共培养降低了促炎反应。Tim-3形状的肠巨噬细胞极化可能是TLR-4依赖性的，因为Tim-3阻断未能加重结肠炎或增加TLR-4 KO模型中的M1巨噬细胞应答。最后，Tim-3信号传导抑制IRF 3的磷酸化，IRF 3是TLR-4下游转录因子，调节巨噬细胞极化。更好地了解这一途径可能会为结肠炎的发病机制提供新的线索，并导致新的治疗策略。(C)2015 Elsevier Inc. All rights reserved.
Tim-3 is involved in the physiopathology of inflammatory bowel disease (IBD), but the underlying mechanism is unknown. Here, we demonstrated that, in mouse with DSS colitis, Tim-3 inhibited the polarization of pathogenic pro-inflammatory M1 macrophages, while Tim-3 downregulation or blockade resulted in an increased M1 response. Adoptive transfer of Tim-3-silenced macrophages worsened DSS colitis and enhanced inflammation, while Tim-3 overexpression attenuated DSS colitis by decreasing the M1 macrophage response. Co-culture of Tim-3-overexpressing macrophages with intestinal lymphocytes decreased the pro-inflammatory response. Tim-3 shaped intestinal macrophage polarization may be TLR-4 dependent since Tim-3 blockade failed to exacerbate colitis or increase M1 macrophage response in the TLR-4 KO model. Finally, Tim-3 signaling inhibited phosphorylation of IRF3, a TLR-4 downstream transcriptional factor regulating macrophage polarization. A better understanding of this pathway may shed new light on colitis pathogenesis and result in a new therapeutic strategy. (C) 2015 Elsevier Inc. All rights reserved.