Neuroinflammation in Spinal Cord Injury: Cellular and Molecular Mechanisms

Abstract: Traumatic spinal cord injury (SCI) elicits a coordinated cascade of innate and adaptive immune responses that evolve from the acute to the chronic phase and strongly influence regeneration and functional outcomes. This review synthesizes phase-specific pathobiology and the roles of microglia and infiltrating macrophages, astrocytes, neutrophils, dendritic cells, and T and B lymphocytes in neuroinflammation. We summarize glial heterogeneity beyond historical binary models, the dual actions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), and central signaling nodes such as NF-κB and the NLRP3 inflammasome. We also highlight how singlecell RNA sequencing and spatial transcriptomics reveal state-specific and region-specific immune programs and identify pathogenic and reparative circuits. These insights support precision immunomodulation tailored to injury stage, region, and cell state, including controlled attenuation of microglial overactivation while preserving debris clearance, redirection of reactive astrocyte states, and modulation of dendritic cell-T-cell crosstalk. Future research should prioritize validating causal immune nodes in vivo and developing biomarker-guided, stage-specific immunotherapies that limit secondary damage and improve neurological recovery after SCI.