MicroRNA-140-5p shuttled by microglia-derived extracellular vesicles attenuates subarachnoid hemorrhage-induced microglia activation and inflammatory response via MMD downregulation

It is documented that microglia-secreted extracellular vesicles (microglia-EVs) exert neuroprotection which is important following subarachnoid hemorrhage (SAH). Herein, we focused on the mechanism of microglia-EVs harboring microRNA-140-5p (miR-140-5p) in SAH development.After the successful establishment of SAH rats, neurological function was evaluated, and behaviors were observed. Serum inflammatory factors (IL-1β and TNF-α) were quantified by ELISA, followed by the detection of microglial polarization by immunofluorescence. The relationship between miR-140-5p and monocyte to macrophage differentiation-associated (MMD) was evaluated using luciferase assay. Following the extraction of microglia and microglia-EVs, the transferring of miR-140-5p by microglia-EVs was assessed by co-culture experiments. SAH rats were treated with the EVs sourced from microglia overexpressing miR-140-5p (microglia-EVs-miR-140-5p) or EVs sourced from miR-140-5p-deficient microglia (microglia-EVs-miR-140-5p inhibitor) for in vivo effect assessment.Microglia-EVs inhibited microglia activation and secretion of TNF-α and IL-1β by delivering miR-140-5p. Microglia-EVs could transmit miR-140-5p into microglia. Furthermore, microglia-EVs-miR-140-5p reduced the expression of its target MMD, resulting in blocked inflammatory response and activation of microglia in SAH rats by disrupting the PI3K/AKT and Erk1/2 signaling.In summary, microglia-EVs transmitted miR-140-5p into microglia to downregulate MMD and finally contributed to neuroprotection in SAH rats.