Dexmedetomidine Mitigates Microglia-Mediated Neuroinflammation through Upregulation of Programmed Cell Death Protein 1 in a Rat Spinal Cord Injury Model.

Excessive neuroinflammation aggravates neurological damage after spinal cord injury (SCI). Controlling neuroinflammation might favor neuroregeneration and tissue repair. Dexmedetomidine is reported to inhibit post-SCI neuroinflammation in previous research. In the current study, to determine the mechanisms by which dexmedetomidine inhibits neuroinflammation, we tested the effect of dexmedetomidine hydrochloride on microglia in vitro and in a rat SCI model. We found that dexmedetomidine hydrochloride up-regulated programmed cell death protein 1 (PD-1), an immunoregulatory molecule, in activated microglia but not in resting microglia. In the presence of programmed death-ligand 1 (PD-L1), this enhanced PD-1 expression downregulated pro-inflammatory cytokine expression and upregulated anti-inflammatory cytokine expression in activated microglia. PD-L1/PD-1 engagement also induced microglia polarization toward the immunoregulatory M2 type. Moreover, dexmedetomidine hydrochloride promoted 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in activated microglia. AMPK signaling was responsible for the above-mentioned changes of cytokine expression and M2 microglia polarization. Consistently, intraperitoneal injection of dexmedetomidine hydrochloride had a similar effect on microglia in the rat SCI model. Taken together, our study disclosed a novel mechanism underlying the anti-neuroinflammatory effect of dexmedetomidine: dexmedetomidine promotes AMPK signaling in activated microglia via upregulation of microglial PD-1 expression, and subsequently drives microglia polarization toward M2 type.