M2 macrophage-derived exosomes mitigate acute inflammation following ischemic stroke.

The acute inflammatory response following ischemic stroke is a key factor in exacerbating brain injury. Modulating excessive inflammation during the oxidative stress (OS) phase represents a potential therapeutic strategy; however, clinical interventions remain limited. M0 and M2 macrophage-derived exosomes (M0-exo and M2-exo) were administered to microglia under oxygen-glucose deprivation/reperfusion (OGD/R) conditions and to mice subjected to transient middle cerebral artery occlusion (tMCAO). The mechanisms underlying their anti-inflammatory effects were then investigated through a combination of bioinformatic analysis and fundamental experiments. Treatment with exosomes markedly suppressed the expression of pro-inflammatory factors. Furthermore, they significantly reduced cerebral infarct volume and improved neurological function in mice. Notably, the anti-inflammatory effect of M2-exo was significantly superior to that of M0-exo. miRNA sequencing and subsequent validation revealed a specific enrichment of miR-330-5p in M2-exo. Mechanistic studies have demonstrated that miR-330-5p suppresses the expression of Spleen tyrosine kinase (Syk) and signal transducer and activator of transcription 3 (Stat3) in microglia, consequently reducing the production of downstream inflammatory factors. Treatment with Syk or Stat3 inhibitors partially mimicked the anti-inflammatory action of miR-330-5p in rescue studies. Our results unveil a novel anti-inflammatory pathway mediated by M2-exo, providing novel insights for stroke therapy.