Celastrol ameliorates experimental autoimmune neuritis by shifting the polarization of M1/M2 macrophages via the hypoxic response pathway

Abstract

BackgroundGBS is an autoimmune disease characterized by inflammatory infiltration and demyelination of peripheral nerves. Macrophage polarization is involved in different stages of GBS. Altering the polarization of macrophages may be an effective therapeutic strategy for GBS. Celastrol was previously shown to contribute to anti-neuroinflammation. However, the mechanism underlying the effect of celastrol in GBS animal model experimental autoimmune neuritis (EAN) is unclear. We hypothesized that celastrol may shift the polarization of macrophages through the NRF /HIF-1αpathway.MethodsClinical scores, weight and histological changes were assessed to investigate the effects of celastrol on EAN. To detect the polarization state of macrophages, flow cytometry and immunofluorescence staining were applied. Inflammation cytokines were evaluated by ELISA. The expression of NRF2 and HIF-1α were detected by western-blot and immunofluorescence staining.ResultsCelastrol treatment significantly ameliorates the severity and neuroinflammation of EAN. The polarization state of macrophages from M1 to M2 was observed upon celastrol application. Consistently, pro-inflammatory cytokines were decreased, whereas anti-inflammatory cytokines were increased upon celastrol treatment. Furthermore, we found that celastrol treatment may increase expression of Nrf2 and decrease the expression of HIF-1α. ConclusionTaken together, these data demonstrate that celastrol may ameliorate the severity and neuroinflammation of EAN via promoting the polarization state of macrophages into M2, likely by modulating the hypoxic response. Celastrol may therefore serve as a novel therapeutic agent for GBS.