Celastrol treatment protects against acute ischemic stroke-induced brain injury by promoting an IL-33/ST2 axis-mediated microglia/macrophage M2 polarization

Mei Jiang, Xinghui Liu, Denghai Zhang, Ying Wang, Xiaoxia Hu, Fengxia Xu, Mingming Jin, Fanfan Cao, Limin Xu

Acute 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. We 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. The 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. Taken together, these data suggest that celastrol post-treatment reduces ischemic stroke-induced brain damage, suggesting celastrol may represent a novel potent pharmacological therapy.