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.
摘要:
脊髓损伤(SCI)可导致严重的运动和感觉缺陷,目前尚无有效的治疗方法。这种损伤的病理过程极其复杂,涉及中枢神经系统中的许多细胞类型。在这项研究中,我们发现了巨噬细胞G蛋白偶联受体激酶相互作用因子1(GIT1)在促进SCI后髓鞘再生和功能修复方面的新功能.使用GIT1flox/floxLyz2-Cre(GIT1CKO)小鼠,我们发现巨噬细胞中的GIT1缺乏导致肿瘤坏死因子-α(TNFα)的产生增加,成熟少突胶质细胞(mOL)比例降低,髓鞘再生受损,体内功能恢复受损。施用可溶性TNF抑制剂可逆转GIT1CKO小鼠中的这些作用。此外,GIT1CWT小鼠骨髓移植逆转了GIT1CKO小鼠的不良后果,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中起关键作用,并在髓鞘碎片刺激后影响少突胶质前体细胞(OPCs)的分化。总的来说,我们的数据揭示了巨噬细胞GIT1在调节OPCs转化为mOLs中的新作用,对于SCI后功能性髓鞘再生至关重要,这表明巨噬细胞GIT1可能是SCI的有希望的治疗靶标。