TNFR2 signaling shapes the sex-specific remyelinating properties of microglia after experimental stroke.

Abstract

Microglial tumor necrosis factor receptor 2 (TNFR2) has emerged as a critical modulator of neuroinflammation and repair following ischemic stroke. Here, we investigated the sex-specific role of TNFR2 in regulating microglial responses during the acute and subacute phases after stroke. Using a conditional knockout model, we found that TNFR2 ablation in microglia exerted opposite effects on morphology, reactivity, and phagocytic capacity in female compared to male mice at day 5 post-stroke. In females, TNFR2 deletion impaired microglial reactivity and myelin debris clearance, reduced oligodendrocyte maturation, and worsened motor and cognitive recovery. In contrast, TNFR2 ablation in males produced milder and occasionally opposing effects, without affecting functional outcomes. Analysis of cerebrospinal fluid from stroke patients revealed a positive association between TNFR2 and microglial phagocytosis markers (TREM2, Galectin-3), particularly in females, which may be useful to track microglial pro-regenerative state during rehabilitation and therapy. These findings identify TNFR2 as a sex-dependent regulator of microglial function and highlight its potential as a therapeutic target for enhancing post-stroke recovery, especially in women.