Modified exosomal SIRPα variants alleviate white matter injury after intracerebral hemorrhage via microglia/macrophages

Abstract

BackgroundDespite limited efficiency, modulation of microglia/macrophages has shown to attenuate neuroinflammation after intracerebral hemorrhage (ICH). In this context, we evaluated the efficacy of modified exosomal signal regulatory protein α (SIRPα) variants (SIRPα-v Exos) in microglia/macrophages and neuroinflammation-associated white matter injury after ICH.MethodsSIRPα-v Exos were engineered to block CD47-SIRPα interactions. After obtaining SIRPα-v Exos from lentivirus-infected mesenchymal stem cells, C57BL/6 mice suffering from ICH underwent consecutive intravenous injections of SIRPα-v Exos (6 mg/kg) for 14 days. Afterwards, the volume of hematoma and neurological dysfunctions were assessed in mice continuously until 35 days after ICH. In addition, demyelination, electrophysiology and neuroinflammation were evaluated. Furthermore, the mechanisms of microglial regulation by SIRPα-v Exos were investigated in vitro under coculture conditions.ResultsThe results demonstrated that the clearance of hematoma in mice suffering from ICH was accelerated after SIRPα-v Exo treatment. SIRPα-v Exos improved long-term neurological dysfunction by ameliorating white matter injury. In addition, SIRPα-v Exos recruited regulatory T cells (Tregs) to promote M2 polarization of microglia/macrophages in the peri-hematoma tissue. In vitro experiments further showed that SIRPα-v Exos regulated primary microglia in a direct and indirect manner in synergy with Tregs.ConclusionOur studies revealed that SIRPα-v Exos could accelerate the clearance of hematoma and ameliorate secondary white matter injury after ICH through regulation of microglia/macrophages. SIRPα-v Exos may become a promising treatment for ICH in clinical practice.Graphical