Journal Article

cGAS Deficiency Regulates the Phenotypic Polarization and Glycolysis of Microglia Through Lactylation in Hypoxic-Ischemic Encephalopathy Cell Model

Wang, Lisheng, Xu, Changli, Cai, Zhonghua, Gu, Qi

2024

Overview

Promoting the M2 phenotype polarization of microglia is of great significance in alleviating hypoxic-ischemic encephalopathy (HIE). The umbilical artery blood sample was collected to evaluate the expression of cGAS, and the aberrant expressed cGAS was verified in the oxygen glucose deprivation (OGD) microglia which was established to mimic HIE in vitro. Then the regulating role of cGAS on the transformation of microglia M2 phenotype polarization and glycolysis was investigated. Moreover, the lactylation of cGAS in OGD treated microglia was evaluated by western blot. cGAS was found to be highly expressed in umbilical artery blood of HIE group, and OGD treated microglia. OGD interference activated microglia into M1 phenotype by enhancing CD86 and suppressing CD206 levels; meanwhile, the microglia in OGD group highly expressed IL-1β, iNOS and TNF-α, and lowly expressed IL-4, IL-10, and Arg-1. Inhibition of cGAS promotes the transformation of microglia from M1 to M2 phenotype. Meanwhile, OGD increased ECAR and decreased OCR to regulate glycolysis, cGAS deficiency inhibits glycolysis in OGD treated microglia. Moreover, the pan lysine lactylation (Pan-Kla) levels and lactated cGAS levels in microglia were upregulated in the OGD group. Lactate reversed the effects of cGAS knockdown on microglia polarization and glycolysis. The present study reveals that the cGAS-mediated neuron injury is associated with high level of cGAS lactylation. Inhibition of cGAS promotes the M2 phenotype polarization of microglia and suppress glycolysis. Thereby, targeting cGAS provides a new strategy for the development of therapeutic agents against HIE.

• Publisher: Springer US,Springer Nature B.V
• Subject: Animals / Biochemistry / Biomedical and Life Sciences / Biomedicine / Blood / blood sampling / CD86 antigen / Development strategies / Encephalopathy / Genetic transformation / Genotype & phenotype / glucose / Glucose - metabolism / Glycolysis / Human Genetics / Humans / Hypoxia / Hypoxia-Ischemia, Brain - genetics / Hypoxia-Ischemia, Brain - metabolism / interleukin-10 / interleukin-4 / Interleukins / Ischemia / lactic acid / Lysine / Medical Microbiology / Mice / Microglia / Microglia - metabolism / neuroglia / neurons / Nitric-oxide synthase / Nucleotidyltransferases - genetics / Nucleotidyltransferases - metabolism / Original Article / oxygen / Pharmacology / Phenotype / Phenotypes / Polarization / therapeutics / Tumor necrosis factor-α / umbilical arteries / Western blotting / Zoology