TREM2 Impairs Glycolysis to Interrupt Microglial M1 Polarization and Inflammation via JAK2/STAT3 Axis.

Abstract

Cerebral ischemia/reperfusion injury (IRI) is a primary pathophysiological basis of ischemic stroke, a dreadful cerebrovascular event carrying substantial disability and lethality. Triggering receptor expressed on myeloid cells 2 (TREM2) is a membrane glycoprotein that has been notified as a protective factor for cerebral ischemic stroke. On this basis, the paper is thereby goaled to interpret the probable activity and downstream mechanism of TREM2 against cerebral IRI. Cerebral IRI was simulated in murine microglial BV2 cells under oxygen-glucose deprivation and reperfusion (OGD/R) conditions. Western blotting ascertained the expressions of TREM2 and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) axis-associated proteins. ELISA and RT-qPCR assayed the secretion of inflammatory cytokines. Immunofluorescence and western blotting estimated macrophage polarization. Glycolysis activation was measured through evaluating lactic acid and extracellular acidification rate (ECAR). RT-qPCR and western blotting examined the expressions of glycolytic genes. TREM2 was abnormally expressed and JAK2/STAT3 axis was aberrantly activated in BV2 cells in response to OGD/R. Elevation of TREM2 repressed the inflammatory reaction and glycolysis, inhibited the JAK2/STAT3 axis, whereas promoted M1-to-M2 polarization in OGD/R-injured BV2 cells. Upregulated TREM2 inactivated the glycolytic pathway to relieve OGD/R-induced inflammatory injury and M1 macrophage polarization. Besides, STAT3 activator, colivelin, aggravated the glycolysis, inflammatory injury and drove M1-like macrophage polarization in TREM2-overexpressing BV2 cells exposed to OGD/R. Collectively, TREM2 might produce anti-inflammatory potential in cerebral IRI, which might dependent on the inactivation of glycolytic pathway via intermediating the JAK2/STAT3 axis.