Abstract
Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release in vitro. However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.
Highlights
Ischemic stroke (IS) is one of the most common causes of mortality and disability worldwide, and an important threat to patient health and quality of life [1]
To explore whether focal cerebral ischemia induces microglial activation, neuroinflammation, rats were subjected to middle cerebral artery occlusion (MCAO)
MCAO was validated by triphenyltetrazolium chloride (TTC) staining, where cortical infarction could be observed 7 days post MCAO (Figure 1A)
Summary
Ischemic stroke (IS) is one of the most common causes of mortality and disability worldwide, and an important threat to patient health and quality of life [1]. Microglia respond rapidly to brain injury including ischemia to produce excessive pro-inflammatory and neuro-modulatory cytokines such as tumor necrosis factor (TNF) and interleukin family members [2, 3]. Gls Regulates Pro-Inflammatory Exosome Release of pro-inflammatory cytokine levels in brain tissue and cerebrospinal fluid (CSF) exacerbates neuroinflammation, which eventually causes neuronal damage [4, 5]. The activated innate immune response acts as a hallmark for the progression of cerebral ischemia injury in which microglia, the resident immune cells of the central nervous system (CNS), play a key role [6]. The activation of microglia is the core of neuroinflammation, which forms the first line of defense for brain injury or disease [7, 8]. It is widely known that microglial activation can be induced by extrinsic factors such as amyloid peptides (Aβ) accumulation, virus infection, and lipopolysaccharide (LPS) stimulation, but the intracellular mechanisms that mediate the activation process remain controversial [9, 10]
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