Rosmarinic Acid Regulates Microglial M1/M2 Polarization via the PDPK1/Akt/HIF Pathway Under Conditions of Neuroinflammation.

Microglia are resident macrophage-like cells in the central nervous system (CNS). The induction of microglial activation dampens neuroinflammation-related diseases by promoting microglial (re)polarization to the anti-inflammatory (M2) phenotype and can serve as a potential therapeutic approach. Mitochondrial respiration and metabolic reprogramming are required for the anti-inflammatory response of M2 macrophages. However, whether these mitochondrial-dependent pathways are involved in microglial (re)polarization to the anti-inflammatory (M2) phenotype under conditions of lipopolysaccharide (LPS)-induced neuroinflammation remains unclear. Moreover, the mechanisms that coordinate mitochondrial respiration and the functional reprogramming of microglial cells have not been fully elucidated. Rosmarinic acid (RA) possesses antioxidative and anti-inflammatory activities, and we previously reported that RA markedly suppresses LPS-stimulated M1 microglial activation in mice. In this study, we found that RA suppresses M1 microglial polarization and promotes microglial polarization to the M2 phenotype under conditions of neuroinflammation. We identified an increase in mitochondrial respiration and found that metabolic reprogramming is required for the RA-mediated promotion of microglial polarization to the M2 phenotype under LPS-induced neuroinflammation conditions. Hypoxia-inducible factor (HIF) subunits are the key effector molecules responsible for the effects of RA on the restoration of mitochondrial function, metabolic reprogramming, and phenotypic polarization to M2 microglia. The phosphoinositide-dependent protein kinase 1 (PDPK1)/Akt/mTOR pathway is involved in the RA-mediated regulation of HIF expression and increase in M2 marker expression. We propose that the inhibition of PDPK1/Akt/HIFs by RA might be a potential therapeutic approach for inhibiting neuroinflammation through the regulation of microglial M1/M2 polarization. Graphical abstract Schematic of the mechanism through which RA suppresses LPS-induced neuroinflammation by promoting microglial polarization to the M2 phenotype via PDPK1/Akt/HIFs. The bold arrows indicate the direction of the effects of RA (i.e., inhibitory or promoting effects on cytokines or mediators).