Physical activity-associated extracellular vesicles inhibit inflammagen-induced microglial activation

Excessive microglial activation and neuroinflammation are pivotal contributors to the progression of neurodegenerative diseases. Physical activity has emerged as a complementary therapy recognized for its anti-inflammatory effects. Long-term treadmill-induced mandatory physical activity (TMPA), a rodent paradigm modeling exercise with controllable intensity, has been shown to reduce age-related microglial activation, dopaminergic neuron degeneration in the substantia nigra, and motor impairments in mice. However, the mechanisms underlying these effects remain unclear. Given the role of physical activity-induced exerkines in modulating anti-inflammatory responses, this study investigated the effects of plasma-derived extracellular vesicles (EVs) from TMPA-treated animals on inflammagen-induced microglial activation in both <i>in vitro</i> and <i>in vivo</i> models. We showed that plasma from TMPA-treated rats suppressed lipopolysaccharide (LPS)-induced inflammatory signaling pathways in BV2 microglia cell line. Within 2 h, over 60% of BV2 microglia internalized EVs, and EVs from rats significantly inhibited LPS-induced microglial activation. <i>In vivo</i>, DiI-labeled EVs from TMPA-treated rats, delivered via tail vein injection, were detected in the brain parenchyma of recipient mice within one day. LPS-treated mice receiving EVs from TMPA-treated rats exhibited significantly lower microglial activation in the substantia nigra compared to those receiving EVs from sedentary rats. These findings demonstrate that physical activity-derived EVs effectively suppress inflammagen-induced microglial activation, providing new insights into their anti-neuroinflammatory properties and potential as therapeutic agents for neuroinflammation-related diseases.