RESUMEN
During the initiation of the inflammatory response of microglia, the expression of many inflammation- and cell metabolism-related genes alters. However, how the transcription of inflammation- and metabolism-related genes are coordinately regulated during inflammation initiation is poorly understood. In this study, we found that LPS stimulation induced the expression of the chromatin target of PRMT1 (protein arginine methyltransferase 1) (CHTOP) in microglia. Knocking down CHTOP in microglia decreased proinflammatory cytokine expression. In addition, CHTOP knockdown altered cell metabolism, as both the upregulated genes were enriched in cell metabolism-related pathways and the metabolites profile was greatly altered based on untargeted metabolomics analysis. Mechanistically, CHTOP could directly bind the regulatory elements of inflammation and cell metabolism-related genes to regulate their transcription. In addition, knocking down CHTOP increased neuronal viability in vitro and alleviated microglia-mediated neuroinflammation in a systemic LPS treatment mouse model. Collectively, these data revealed CHTOP as a novel regulator to promote microglia-mediated neuroinflammation by coordinately regulating the transcription of inflammation and cell metabolism-related genes.
Asunto(s)
Microglía , Enfermedades Neuroinflamatorias , Animales , Ratones , Expresión Génica , Inflamación/metabolismo , Lipopolisacáridos/metabolismo , Microglía/metabolismoRESUMEN
RNA splicing is a post-transcriptional event that regulates many physiological and pathological events. However, whether RNA splicing regulates cerebral I/R-induced brain injury remains largely unknown. In this study, we found that the chromatin target of Prmts (CHTOP) was highly expressed in neurons, and anti-inflammatory cytokine interleukin-10 (IL-10) upregulates its expression after ischemia. In addition, overexpression or knockdown of CHTOP alleviated or exacerbated neuronal death in both experimental stroke mice and cultured neurons. Mechanistically, RNA alternative splicing is altered early after oxygen and glucose deprivation/reoxygenation (OGD/R). CHTOP interacted with nuclear speckle-related proteins to regulate alternative mRNA splicing of neuronal survival-related genes after OGD/R. In addition, I/R injury-induced cytokines IL-10 regulate CHTOP-mediated RNA splicing to alleviate ischemic brain injury. Taken together, this study reveals the alteration of RNA splicing after OGD/R and identifies the IL-10-CHTOP-RNA splicing axis as a modulator of brain injury, which may be promising therapeutic targets for ischemic stroke.