Abstract
BackgroundAcute ischemic stroke (AIS) is the most common type of cerebrovascular disease and is a leading cause of disability and death worldwide. Recently, a study suggested that transformation of microglia from the pro-inflammatory M1 state to the anti-inflammatory and tissue-reparative M2 phenotype may be an effective therapeutic strategy for ischemic stroke. Celastrol, a traditional oriental medicine, may have anti-inflammatory and neuroprotective effects. However, the underlying mechanisms remain unknown.MethodsWe first determined the expression levels of inflammatory factors in patients and rodent models associated with AIS; we then determined the anti-inflammatory effects of celastrol in AIS, both in vivo and in vitro, using animal models of middle cerebral artery occlusion (MCAO) and cell models of oxygen-glucose deprivation (OGD) treatment with or without celastrol, respectively.ResultsThe results indicated that expression of both inflammatory (interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α) cytokines, as well as the anti-inflammatory cytokine, IL-33, and IL-10, were increased following AIS in patients and in animal models. Furthermore, in vitro experiments confirmed that celastrol treatment decreased inflammatory cytokine expression induced by OGD through an IL-33/ST2 axis-mediated M2 microglia/macrophage polarization. Finally, celastrol is protected against ischemic-induced nerve injury, both in vivo and in vitro.ConclusionsTaken together, these data suggest that celastrol post-treatment reduces ischemic stroke-induced brain damage, suggesting celastrol may represent a novel potent pharmacological therapy.
Highlights
Acute ischemic stroke (AIS) is the most common type of cerebrovascular disease and is a leading cause of disability and death worldwide
The results indicate that celastrol does have protective effects against AIS-induced injury and that these effects are related to an interleukin 33 (IL-33)/stimulation expressed gene 2 (ST2) axis-mediated microglia/macrophage M2 polarization
Serum IL-33 levels and inflammatory factor levels are increased in stroke patients Clinical test results showed that AIS did not alter blood Hb, red blood cells (RBC), or PLT counts, whereas a significant 70.5% increase in the white blood cells (WBC) count was observed in patients suffering from AIS compared to the control values (Table 1)
Summary
Acute ischemic stroke (AIS) is the most common type of cerebrovascular disease and is a leading cause of disability and death worldwide. A study suggested that transformation of microglia from the pro-inflammatory M1 state to the anti-inflammatory and tissue-reparative M2 phenotype may be an effective therapeutic strategy for ischemic stroke. Increasing evidence indicates that microglia and infiltrated macrophages play critical roles in regulating the immune and inflammatory responses after brain injuries [7]. IL-33 expression in brain tissue improved ischemic-induced brain injury by promoting M2 phenotype polarization and suppressing Th17 responses in mice [12]. Another recent study found that IL-33/growth stimulation expressed gene 2 (ST2) signaling activated beneficial M2 macrophage polarization after ischemia and subsequently reduced neuronal cell death. ST2 (growth stimulation expressed gene 2) is a member of the IL-1 receptor superfamily and is expressed on cardiomyocytes, as well as a large variety of immune cells, including M2 macrophages [13]
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