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

Background: Despite 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 a (SIRP alpha) variants (SIRP alpha-v Exos) in microglia/macrophages and neuroinflammation-associated white matter injury after ICH. Methods: SIRP alpha-v Exos were engineered to block CD47-SIRP alpha interactions. After obtaining SIRP alpha-v Exos from lentivirus-infected mesenchymal stem cells, C57BL/6 mice suffering from ICH underwent consecutive intravenous injections of SIRP alpha-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 microglia) regulation by SIRP alpha-v Exos were investigated in vitro under coculture conditions. Results: The results demonstrated that the clearance of hematoma in mice suffering from ICH was accelerated after SIRP alpha-v Exo treatment. SIRP alpha-v Exos improved long-term neurological dysfunction by ameliorating white matter injury. In addition, SIRP alpha-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 SIRP alpha-v Exos regulated primary microglia in a direct and indirect manner in synergy with Tregs. Conclusion: Our studies revealed that SIRP alpha-v Exos could accelerate the clearance of hematoma and ameliorate secondary white matter injury after ICH through regulation of microglia/macrophages. SIRP alpha-v Exos may become a promising treatment for ICH in clinical practice.

Automated summary

The study found that SIRP alpha-v Exos accelerated the clearance of hematoma and improved neurological function in patients with ICH. Additionally, SIRP alpha-v Exos promoted polarization of microglia/macrophages and recruited regulatory T cells. The experiments demonstrated the therapeutic effects of SIRP alpha-v Exos in treating ICH by regulating microglia/macrophages.