Rosmarinic Acid Regulates Microglial M1/M2 Polarization via the PDPK1/Akt/HIF Pathway Under Conditions of Neuroinflammat
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ORIGINAL ARTICLE
Rosmarinic Acid Regulates Microglial M1/M2 Polarization via the PDPK1/Akt/HIF Pathway Under Conditions of Neuroinflammation Yicong Wei,1 Jianxiong Chen,1 Guo-En Cai,2 Wei Lu,1 Wei Xu,1 Ruiguo Wang,1 Yu Lin ,1,3,4 and Chengzi Yang1,3,4
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
Abstract—
Yicong Wei and Jianxiong Chen contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-020-01314-w) contains supplementary material, which is available to authorized users. 1
College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China 2 Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China 3 Fujian University of Traditional Chinese Medicine, No. 1 Qiuyang Road, Minhou Shangjie, Fuzhou, China 4 To whom correspondence should be addressed at Fujian University of Traditional Chinese Medicine, No. 1 Qiuyang Road, Minhou Shangjie, Fuzhou, China. E-mails: [email protected]; [email protected] Abbreviations CNS, Central nervous system; LPS, Lipopolysaccharide; HIF, Hypoxia-inducible factor; MS, Multiple sclerosis; AD, Alzheimer’s disease; PD, Parkinson’s disease; TNF-α, Tumor necrosis factor-α; IL, Interleukin; iNOS, Inducible nitric oxide synthase; IFN-γ, Interferon-
gamma; Arg1, Arginase-1; Ym-1, Chitinase 3–like 3; Fizz-1, Inflammatory zone 1; TGF-β, Transforming growth factor β; MRC1, Mannose receptor C type 1; CD206, Mannose receptor; CD163, Scavenger receptor; RA, Rosmarinic acid; PPP, Pentose phosphate pathway; ATP, Adenosine triphosphate; ROS, Reactive oxygen species; NO, Nitric oxide; TCA, Tricarboxylic acid; ACLY, ATP-citrate lyase; PDPK1, Phosphoinositidedependent protein kinase 1; PDK3, Pyruvate dehydrogenase kinas
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