TIM-3-dependent lysosome biogenesis is required for myelin debris clearance in macrophages

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ID: 313906
2026
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Abstract
Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the immune-mediated demyelination and neurodegeneration of the central nervous system. Phagocyte mediated myelin debris clearance is required for remyelination. TIM-3 is highly expressed on mononuclear macrophages and promotes the phagocytosis of apoptotic cells. Here, we report that TIM-3 enhances the clearance of myelin debris in experimental autoimmune encephalomyelitis (EAE), a model of MS. Tim-3 knockout (KO) exacerbated EAE severity, neuroinflammation, and demyelination by regulating mononuclear macrophages. TIM-3 promoted the phagocytosis and degradation of myelin debris by macrophages. Mechanistically, Tim-3 deficiency impaired lysosomal biogenesis and function, leading to lysosomal membrane permeabilization and disrupted lysosomal acidification, which further exacerbated neuroinflammation and demyelination. Notably, TIM-3 blocked the interaction of mTOR-TFEB to inhibit TFEB phosphorylation and facilitate its nuclear translocation, followed by increased expression of lysosomal genes critical for myelin degradation. Importantly, the IgV domain is necessary in TIM-3-mediated lysosomal regulation and myelin degradation. These findings highlight TIM-3 as a key regulator of lysosomal homeostasis and the clearance of myelin debris, suggesting that the IgV domain has promise as a therapeutic agent for treating demyelinating diseases such as MS.
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Authors Xiaodi Zhang, Ziqing Xu, Yingxue Zhang, Tong Zheng, Xiaolei Ren, Ying Xiao, Hao Chen, Na Han, C L Li, Xuetian Yue, Zhuanchang Wu, Xiaohong Liang, Ma Cl, Pin Wang, Gao L
Journal Brain research
Year 2026
DOI
10.1093/brain/awag170
URL
https://doi.org/10.1093/brain/awag170
Keywords Keywords not found

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