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

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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.

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).

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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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Funding

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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Author notes

  1. Yicong Wei and Jianxiong Chen contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

    Yicong Wei, Jianxiong Chen, Wei Lu, Wei Xu, Ruiguo Wang, Yu Lin & Chengzi Yang

  2. Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China

    Guo-En Cai

  3. Fujian University of Traditional Chinese Medicine, No. 1 Qiuyang Road, Minhou Shangjie, Fuzhou, China

    Yu Lin & Chengzi Yang

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  1. Yicong Wei
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The study does not involve human participants, human data, or human tissue. All the animal experiments were performed in accordance with the guidelines of the National Institutes of Health Guide concerning the care and use of laboratory animals. The procedures for this study were approved by the Animal Care and Use Committee of Fujian University of Traditional Chinese Medicine.

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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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