Macrophage GIT1 promotes oligodendrocyte precursor cell differentiation and remyelination after spinal cord injury

IF 5.4 2区 医学 Q1 NEUROSCIENCES Glia Pub Date : 2024-06-20 DOI:10.1002/glia.24577
Hao Liu, Jiang Yi, Chenxi Zhang, Yin Li, Qian Wang, Shenyu Wang, Siming Dai, Ziyang Zheng, Tao Jiang, Peng Gao, Ao Xue, Zhenfei Huang, Fanqi Kong, Yongxiang Wang, Baorong He, Xiaodong Guo, Qingqing Li, Jian Chen, Guoyong Yin, Shujie Zhao
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Abstract

Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.

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巨噬细胞 GIT1 促进脊髓损伤后少突胶质前体细胞分化和髓鞘再形成
脊髓损伤(SCI)可导致严重的运动和感觉障碍,目前尚无有效的治疗方法。这种损伤的病理过程极其复杂,涉及中枢神经系统的多种细胞类型。在这项研究中,我们发现了巨噬细胞 G 蛋白偶联受体激酶-互作因子 1(GIT1)在促进髓鞘再形成和 SCI 后功能修复方面的新功能。利用GIT1flox/flox Lyz2-Cre(GIT1 CKO)小鼠,我们发现巨噬细胞中GIT1的缺乏会导致肿瘤坏死因子-α(TNFα)生成增加、成熟少突胶质细胞(mOLs)比例降低、髓鞘再形成受损以及体内功能恢复受损。给GIT1 CKO小鼠注射可溶性TNF抑制剂后,这些影响被逆转。此外,GIT1 CWT 小鼠的骨髓移植可逆转 GIT1 CKO 小鼠的不良结果,这进一步表明巨噬细胞 GIT1 在调节脊髓损伤修复中的作用。我们的体外实验表明,巨噬细胞GIT1在分泌TNFα方面起着关键作用,并在髓鞘碎片刺激后影响少突胶质前体细胞(OPCs)的分化。总之,我们的数据揭示了巨噬细胞 GIT1 在调节 OPCs 向 mOLs 转化过程中的新作用,而 mOLs 是 SCI 后功能性髓鞘再形成所必需的,这表明巨噬细胞 GIT1 可能是 SCI 的一个有前途的治疗靶点。
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来源期刊
Glia
Glia 医学-神经科学
CiteScore
13.10
自引率
4.80%
发文量
162
审稿时长
3-8 weeks
期刊介绍: GLIA is a peer-reviewed journal, which publishes articles dealing with all aspects of glial structure and function. This includes all aspects of glial cell biology in health and disease.
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