Ferrostatin-1 Polarizes Microglial Cells Toward M2 Phenotype to Alleviate Inflammation After Intracerebral Hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is one of the most lethal stroke types and lacks effective therapeutic regimens. Recently, evidence has suggested the involvement of the ferroptosis inhibitor ferrostatin-1 (Fer-1) in the pathophysiological process of ICH. In this study, we examined the underlying mechanism.MethodsWe induced an in vitro apoptosis model in organotypic hippocampal slice (OHS) using hemoglobin (Hb) and an in vivo ICH model using collagenase. OHSs were treated with MK-801, Fer-1, glutamate, and Hb to assess the impacts of Fer-1 on neuron apoptosis, glutathione peroxidase-4 activity, reactive oxygen species production, inflammation-related factors, expression of M1 markers and M2 markers, and the phagocytic function of microglial cells in vitro. Then, ICH mice were treated with Fer-1 and ruxolitinib to evaluate the effects of Fer-1-orchestrating janus kinase 1/signal transducer and activator of transcription 6 pathway on neurological function, brain water content, hematoma volume, the anti-inflammatory factor, M1 and M2 markers, and the phagocytic function of microglial cells in vivo.ResultsHb or glutamate facilitated glutathione peroxidase dysfunction, reactive oxygen species production, and neuronal apoptosis in OHSs, which was nullified by Fer-1. Fer-1 polarized microglial cells to the M2 phenotype, enhanced their phagocytic function, and prevented inflammation in Hb-induced OHSs. In the ICH mouse model, Fer-1 was found to improve neurological function and promote hematoma absorption. In addition, Fer-1 activated the Fer-1-orchestrating janus kinase 1/signal transducer and activator of transcription 6 pathway, which accelerated microglial M2 polarization, enhanced the phagocytic function of microglial cells, and restrained inflammation in ICH mice.ConclusionsOverall, our findings suggest that Fer-1 may be a novel mechanism underlying microglial M2 polarization and inflammation after ICH.