TREM2 Facilitates Myelin Debris Clearance but Exacerbates Chronic Inflammation and Fibrosis After Spinal Cord Injury

The accumulation of myelin debris after spinal cord injury (SCI) inhibits axon regeneration and remyelination. Triggering receptor expressed on myeloid cell 2 (TREM2) is crucial for cellular debris clearance and disease-associated microglia (DAM) activation. However, whether TREM2 mediates these processes after SCI remains unclear.

A mouse model of spinal cord crush injury was employed. Female TREM2^-/- mice were used to delete TREM2, while COG1410 was administered to activate TREM2 in female wild-type mice. Tissue immunostaining and western blotting were performed to analyze TREM2 expression after SCI. Tissue immunostaining was conducted to evaluate the cellular origin of TREM2 and its impact on phagocytosis, foamy macrophage formation, DAM activation, axon regeneration, and neuronal survival. Basso Mouse Scale and footprint analysis were used to evaluate locomotor function recovery.

TREM2 was primarily localized to Iba1⁺ macrophages/microglia around the lesion core, with its expression increasing during the subacute stage, peaking at 7 days post-injury. TREM2 deficiency impaired engulfment and degradation of myelin debris, increased foamy macrophage formation, and hindered DAM activation. In vivo rescue experiments further confirmed that TREM2 promotes DAM activation via the PI3K/AKT pathway. However, TREM2 exacerbated fibrosis, as indicated by increased extracellular matrix deposition, enhanced fibroblast accumulation, and widespread inflammation. COG1410-mediated long-term activation of TREM2 impaired long-term locomotor function recovery, inhibited axon regeneration, and reduced neuronal survival, whereas short-term activation improved early locomotor function without structural neuroprotection.

Our study suggests that TREM2 promotes myelin debris clearance but exacerbates chronic inflammation and fibrosis after SCI. These findings underscore the promise of TREM2 as a target for developing effective treatment strategies for SCI.