Regulatory T cells promote functional recovery after spinal cord injury by alleviating microglia inflammation via STAT3 inhibition

Background: Immediately after spinal trauma, immune cells, and proinflammatory cytokines infiltrate the spinal cord and disrupt the focal microenvironment, which impedes axon regeneration and functional recovery. Previous studies have reported that regulatory T cells (Tregs) enter the central nervous system and exert immunosuppressive effects on microglia during multiple sclerosis and stroke. However, whether and how Tregs interact with microglia and modulate injured microenvironments after spinal cord injury (SCI) remains unknown.

Method: Regulatory T cells spatiotemporal characteristics were analyzed in a mouse contusion SCI model. Microglia activation status was evaluated by immunostaining and RNA sequencing. Cytokine production in injured spinal cord was examined using Luminex. The role of STAT3 in Treg-microglia crosstalk was investigated in a transwell system with isolated Tregs and primary microglia.

Results: Regulatory T cells infiltration of the spinal cord peaked on day 7 after SCI. Treg depletion promoted microglia switch to a proinflammatory phenotype. Inflammation-related genes, such as ApoD, as well as downstream cytokines IL-6 and TNF-α were upregulated in microglia in Treg-depleted mice. STAT3 inhibition was involved in Treg-microglia crosstalk, and STAT3 chemical blockade improved function recovery in Treg-depleted mice.

Conclusion: Our results suggest that Tregs promote functional recovery after SCI by alleviating microglia inflammatory reaction via STAT3.

STAT3; Treg; injured microenvironment; microglia; neuroinflammation; spinal cord injury.