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

• Published in: Glia 2024-09, Vol.72 (9), p.1674-1692
• Main Authors: Liu, Hao, Yi, Jiang, Zhang, Chenxi, Li, Yin, Wang, Qian, Wang, Shenyu, Dai, Siming, Zheng, Ziyang, Jiang, Tao, Gao, Peng, Xue, Ao, Huang, Zhenfei, Kong, Fanqi, Wang, Yongxiang, He, Baorong, Guo, Xiaodong, Li, Qingqing, Chen, Jian, Yin, Guoyong, Zhao, Shujie
• Format: Article
• Language: English
• Subjects: Animals; Bone marrow; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell differentiation; Cell Differentiation - physiology; Central nervous system; Differentiation (biology); Disease Models, Animal; Extreme values; Female; Flox; GIT1; Glial stem cells; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Kinases; macrophage; Macrophages; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myelin; Myelination; oligodendrocyte; Oligodendrocyte Precursor Cells - metabolism; Oligodendrocytes; Oligodendroglia - metabolism; Precursors; Recovery of function; Recovery of Function - physiology; Remyelination - physiology; Spinal cord injuries; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - pathology; spinal cord injury; TNF inhibitors; TNFα; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.24577

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. Main Points Macrophage GIT1 inhibits TNFα secretion and facilitates the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (mOLs), thereby contributing to remyelination and improving functional recovery in mice after spinal cord injury. ‘The role of macrophage GIT1 in spinal cord injury repair’.