Hydrogen gas inhibits neuroinflammation after traumatic brain injury by promoting microglia M2 polarization via AMPK-dependent mediation of HDAC5

Abstract

Abstract Microglia-associated neuroinflammation plays a role in secondary brain injury after traumatic brain injury (TBI). Hydrogen gas (H2) promotes microglial M2 polarization and alleviates neuroinflammation across brain disorders. However, little is known about the mechanism and target of H2 in treating neuroinflammation of TBI. In the present study, H2 inhalation conferred an improved neurological outcome after TBI by significantly decreasing neuroinflammation and activating microglial M2 polarization via inhibition of histone deacetylase 5 (HDAC5) expression. Furthermore, an AMPK inhibitor activated expression of HDAC5 and downstream GSK3β/AKT signaling; H2 treatment reversed these effects and rescued neurological function in vitro and in vivo. Mechanistically, H2 down-regulated GSK3β histone H3 acetylation levels through AMPK activation. Altogether, these data indicate that H2 inhalation inhibits neuroinflammation and rescues neurological function after TBI by promoting M2 polarization of microglia through GSK3β/AKT signaling and AMPK-dependent mediation of HDAC5. Our findings reveal novel targets for inhibiting neuroinflammation, and highlights the potential of H2 therapy for TBI.