Abstract
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.
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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:
-
Phosphoinositide-dependent protein kinase 1
- PDK3:
-
Pyruvate dehydrogenase kinase 3
- qRT-PCR:
-
Quantitative real-time PCR
- OM:
-
Oligomycin
- FAO:
-
Glucose and fatty acid oxidation
- 2-DG:
-
2-Deoxy-glucose
- ETO:
-
Etomoxir
- PDK1:
-
Pyruvate dehydrogenase kinase 1
- LDHA:
-
Lactate dehydrogenase A
- PDH:
-
Pyruvate dehydrogenase
- DMOG:
-
Dimethyloxaloylglycine
- TLR4:
-
Toll-like receptor 4
- CD14:
-
Cluster of differentiation 14
- JNK:
-
c-Jun N-terminal kinase
- NF-κB:
-
Nuclear factor-kappa B
- NLRP3:
-
NOD-like receptor family pyrin domain-containing 3
- TPI:
-
Triosephosphate isomerase
- HK2:
-
Hexokinase 2
- PKM:
-
Enolase 1 and pyruvate kinase muscle
- TSC:
-
Tuberous sclerosis complex
- GLUT1:
-
Glycose transporter 1
- OXPHOX:
-
Oxidative phosphorylation
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Acknowledgments
The authors would like to acknowledge the staff of the Animal Centre of the Fujian University of Traditional Chinese Medicine for their excellent technical support.
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This work was financially supported by grants from the Fujian Provincial Health and Family Planning Commission (Grant No. 2018-ZQN-66) and the Department of Technology and Science of the Fujian Provincial Government (Grant No. 2018 J01869).
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Wei, Y., Chen, J., Cai, GE. et al. Rosmarinic Acid Regulates Microglial M1/M2 Polarization via the PDPK1/Akt/HIF Pathway Under Conditions of Neuroinflammation. Inflammation 44, 129–147 (2021). https://doi.org/10.1007/s10753-020-01314-w
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DOI: https://doi.org/10.1007/s10753-020-01314-w