2. Academic Validation
  3. FTO alleviates cerebral ischemia/reperfusion-induced neuroinflammation by decreasing cGAS mRNA stability in an m6A-dependent manner

FTO alleviates cerebral ischemia/reperfusion-induced neuroinflammation by decreasing cGAS mRNA stability in an m6A-dependent manner

  • Cell Signal. 2023 Jun 13;110751. doi: 10.1016/j.cellsig.2023.110751.
Zhiyong Yu 1,  Linbo Zheng 2,  Yan Geng 3,  Yuting Zhang 1,  Yupeng Wang 1,  Guoxing You 1,  Mingsheng Cai 4,  Meili Li 5,  Xiao Cheng 6,  Jie Zan 7
Affiliations

Affiliations

  • 1 School of Biomedical and Pharmaceutical sciences, Guangdong University of Technology, Guangzhou 510006, China.
  • 2 Department of Traditional Chinese Medicine, Guangdong Second Provincial General Hospital, Guangzhou 510310, China; School of Biomedical and Pharmaceutical sciences, Guangdong University of Technology, Guangzhou 510006, China.
  • 3 School of Biomedical and Pharmaceutical sciences, Guangdong University of Technology, Guangzhou 510006, China; School of Biomedical and Pharmaceutical sciences, Guangdong University of Technology, Guangzhou 510006, China.
  • 4 State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology; Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.
  • 5 State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology; Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 510260, Guangdong, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China; Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China. Electronic address: [email protected].
  • 7 School of Biomedical and Pharmaceutical sciences, Guangdong University of Technology, Guangzhou 510006, China; Department of Traditional Chinese Medicine, Guangdong Second Provincial General Hospital, Guangzhou 510310, China. Electronic address: [email protected].
PMID: 37321527 DOI: 10.1016/j.cellsig.2023.110751
Abstract

Microglia-mediated inflammation is a major contributor to the brain damage in cerebral ischemia and reperfusion (I/R) injury, and N6-Methyladenosine (m6A) has been implicated in cerebral I/R injury. Here, we explored whether m6A modification is associated with microglia-mediated inflammation in cerebral I/R injury and its underlying regulatory mechanism using an in vivo mice model of intraluminal middle cerebral artery occlusion/reperfusion (MCAO/R) and in vitro models of primary isolated microglia and BV2 microglial cells subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) were used. We found microglial m6A modification increased and microglial fat mass and obesity-associated protein (FTO) expression decreased in cerebral I/R injury in vivo and in vitro. Inhibition of m6A modification by intraperitoneal injection of Cycloleucine (Cyc) in vivo or transfection of FTO plasmid in vitro significantly alleviated brain injury and microglia-mediated inflammatory response. Through Methylated RNA immunoprecipitation sequencing (MeRIP-Seq), RNA sequencing (RNA-Seq) and western blotting, we found that m6A modification promoted cerebral I/R-induced microglial inflammation via increasing cGAS mRNA stability to aggravate STING/NF-κB signaling. In conclusion, this study deepens our understanding on the relationship of m6A modification and microglia-mediated inflammation in cerebral I/R injury, and insights a novel m6A-based therapeutic for inhibiting inflammatory response against ischemic stroke.

Keywords

Cerebral ischemia and reperfusion injury; Cyclic GMP-AMP synthase; Fat mass and obesity-associated protein; Inflammation; N6-Methyladenosine.

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