The role of microglial Tim-3 in neuroinflammation and functional recovery after spinal cord injury

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Abstract
Aims: T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3), an immune checkpoint molecule, is highly expressed in microglia and its expression dynamically increases during central nervous system (CNS) development. Although its immunomodulatory functions are well-established, its role in inflammation following spinal cord injury (SCI) remains unclear. This study aimed to elucidate the regulatory role of microglial Tim-3 in the sterile inflammatory response after SCI and to explore its potential as a therapeutic target. Materials and methods: A SCI model was established using C57BL/6 mice. Microglial Tim-3 function was investigated through adeno-associated virus-mediated Tim-3 overexpression and intervention with the Nrf2 agonist Oltipraz. Luxol fast blue (LFB) and Nissl staining were used to assess lesional area and tissue structure. Basso Mouse Scale (BMS) scoring and the sucrose preference test (SPT) were employed to evaluate motor function recovery and depressive-like behavior. Immunofluorescence was performed to analyze glial activation and neurodegeneration. Expression levels of inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA) and western blot (WB). Key findings: Microglia-specific Tim-3 overexpression promoted microglial proliferation and activation, inducing upregulation of iNOS and robust production of pro-inflammatory cytokines. This exacerbated neural tissue damage and motor dysfunction, whereas depressive-like behaviors were not significantly affected. These effects were partially reversed by the Nrf2 agonist. Significance: AAV-mediated microglial Tim-3 overexpression exacerbates neuroinflammation and functional impairment after SCI, potentially through an association with the Nrf2/HMGB1 signaling axis. Targeting microglial Tim-3 may represent a promising therapeutic strategy for SCI.

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