Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

Abstract

Background Neuroinflammation is the major pathogenesis of cerebral ischemia. Microglia are activated and polarized to either the pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype, which act as a critical mediator of neuroinflammation. Sestrin2 has pro-survival properties against ischemic brain injury. However, whether sestrin2 has an anti-inflammatory function by shifting microglia polarization and its underlying mechanism is unknown. Methods Adult male C57BL/6 mice (N = 108) underwent transient middle cerebral artery occlusion (tMCAO) and were treated with exogenous sestrin2. Neurological deficit scores and infarct volume were determined. Cell apoptosis was examined by TUNEL staining and Western blotting. The expression of inflammatory mediators, M1/M2-specific markers, and signaling pathways were detected by reverse transcription-polymerase chain reaction, immunostaining, and Western blotting. To explore the underlying mechanism, primary neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with oxygenated condition medium of BV2 cells incubated with different doses of sestrin2. Results Sestrin2 attenuated the neurological deficits, infarction volume, and cell apoptosis after tMCAO compared to those in the control (p < 0.05). Sestrin2 had an anti-inflammatory effect and could suppress M1 microglia polarization and promote M2 microglia polarization. Condition medium from BV2 cells cultured with sestrin2 reduced neuronal apoptosis after OGD in vitro. Furthermore, we demonstrated that sestrin2 drives microglia to the M2 phenotype by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway and restoring autophagic flux. Conclusions Sestrin2 exhibited neuroprotection by shifting microglia polarization from the M1 to M2 phenotype in ischemic mouse brain, which may be due to suppression of the mTOR signaling pathway and the restoration of autophagic flux.

Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway

“…Nissl staining was used to measure volume of infarct [ 26 ]. Briefly, the coronal cryosections of the brain (20-μm thick, 1-mm intervals) were stained with cresyl violet (Cat.…”

“…6a). (2) We further investigated the effect of Ac2-26-mediated microglial polarization on post-I/R neuronal apoptosis using previously published methods [26,27]. HT22 cells were subjected to OGD injury for 2 h, and then incubated with CM collected from OGD/Rstimulated BV2 cells with different treatments (collected from experiment 1) at the start of reoxygenation (Fig.…”

Ganoderic Acid A-Mediated Modulation of Microglial Polarization is Involved in Depressive-Like Behaviors and Neuroinflammation in a Rat Model of Post-Stroke Depression

“…M1/ M2 phenotype microglia acts as critical mediators in the pathological process of neuroinflammation. 33 In addition, M1/M2 microglial polarization is associated with psychiatric disorders. 9 Inhibition of M1 microglial polarization and promotion of M2 microglial polarization contribute to the antidepressant therapies.…”

Potential Roles of Sestrin2 in Alzheimer’s Disease: Antioxidation, Autophagy Promotion, and Beyond

“…Stroke is the most common age-related cerebral vascular disease and the chief cause of physical and intellectual disability in adults, as well as the leading cause of mortality in developed countries [79]. Several studies have investigated the roles of sestrin2 in cerebral ischemia [80][81][82][83]. It was demonstrated that sestrin2 can activate the Nrf2/heme oxygenase-1 (HO-1) pathway, leading to augmentation of angiogenesis following focal cerebral ischemia [82].…”