The semaphorin 4A-neuropilin 1 axis alleviates kidney ischemia reperfusion injury by promoting the stability and function of regulatory T cells
The semaphorin 4A-neuropilin 1 axis alleviates kidney ischemia reperfusion injury by promoting the stability and function of regulatory T cells
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信号蛋白4A-神经毡蛋白1轴通过促进调节性T细胞的稳定性和功能减轻肾脏缺血再灌注损伤
DOI：
10.1016/j.kint.2021.08.023
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发表时间：
2021
影响因子：
19.6
通讯作者：
Ming Cai
中科院分区：
文献类型：
--
作者：
Junnan Xu;Xiubin Li;Qing Yuan;Chenfeng Wang;Liang Xu;Xing Wei;Haitao Liu;Bo Yu;Zhekun An;Yuanyu Zhao;Xiang Li;Xu Zhang;Xin Ma;Ming Cai
先前的研究表明，CD4+Foxp3+调节性T细胞（Tregs）通过其免疫抑制特性对肾缺血再灌注损伤具有保护作用。不幸的是，Tregs在肾缺血再灌注损伤中的相关机制尚未完全阐明。信号蛋白4A （Sema4A）对于维持肿瘤中Tregs的免疫抑制能力至关重要。然而，Sema4A是否能通过Tregs减轻肾脏缺血再灌注损伤尚未得到证实。本研究探讨Sema4A在肾脏缺血再灌注损伤发生中的作用及机制。在缺血再灌注损伤前给予重组人Sema4A-Fc嵌合体蛋白可促进Tregs的扩增和功能，减少中性粒细胞和促炎巨噬细胞的积累，从而减轻损伤肾脏的功能和组织学损伤。Tregs的缺失使Sema4A对肾缺血再灌注损伤的保护作用消失，提示Tregs是Sema4A在肾缺血再灌注损伤发展过程中的主要靶细胞类型。从机制上讲，Sema4A与神经匹素1 （Nrp1）结合，Nrp1是Sema4A和其他配体的细胞表面受体，也是Tregs的关键调节因子，然后促进磷酸酶和紧张素同源物的募集，抑制oxp3cremice的Akt-mTOR通路，但不抑制inrp1f /fFoxp3Cremice。同样，Treg特异性缺失Nrp1会阻断Sema4A对Treg细胞扩增和功能的影响。因此，我们的研究结果表明，Sema4A-Nrp1轴通过促进小鼠肾脏Tregs的稳定性和功能来缓解缺血再灌注损伤的发展。
Previous studies have suggested the role of CD4+Foxp3+regulatory T cells (Tregs) in protection against kidney ischemia reperfusion injury via their immunosuppressive properties. Unfortunately, the associated mechanisms of Tregs in kidney ischemia reperfusion injury have not been fully elucidated. Semaphorin 4A (Sema4A) is essential for maintaining the immunosuppressive capacity of Tregs in tumors. However, whether Sema4A can alleviate kidney ischemia reperfusion injury through Tregs has not yet been demonstrated. Here, we investigated the effect and mechanism of Sema4A on the development of kidney ischemia reperfusion injury. Administration of recombinant human Sema4A-Fc chimera protein prior to ischemia reperfusion injury promoted the expansion and function of Tregs and decreased the accumulation of neutrophils and proinflammatory macrophages thereby attenuating functional and histological injury of the injured kidneys. Depletion of Tregs abrogated the protective effect of Sema4A on kidney ischemia reperfusion injury, suggesting Tregs as the main target cell type for Sema4A in the development of this injury. Mechanistically, Sema4A bound to neuropilin 1 (Nrp1), a cell surface receptor for Sema4A and other ligands and a key regulator of Tregs, which then promoted recruitment of phosphatase and tensin homologue and suppressed the Akt–mTOR pathway inFoxp3Cremice but not inNrp1f/fFoxp3Cremice. Consistently, Treg-specific deletion of Nrp1 blocked the effect of Sema4A on the expansion and function of Treg cells. Thus, our results demonstrate that the Sema4A–Nrp1 axis alleviates the development of ischemia reperfusion injury by promoting the stability and function of Tregs in mouse kidneys.