Circulating Pro-Inflammatory Exosomes Worsen Stroke Outcomes In Aging

Rationale: The systemic inflammatory milieu plays an important role in the age-related decline in functional integrity, but its contribution to age-related disease (eg, stroke) remains largely unknown. Objective: To determine the role of systemic inflammatory milieu in ischemic stroke. Methods and Results: Here, we report that systemic administration of serum exosomes from young rats into aged ischemic rats improved short- and long-term functional outcomes after ischemic stroke and reduced synaptic loss. By contrast, similar injections of serum exosomes from aged rats into aged ischemic rats worsened sensorimotor deficits through exacerbation of synaptic dysfunction due to excessive microglial phagoptosis (primary phagocytosis). Our proteomic analysis further revealed that the expression of CD46, a C3b/C4b-inactivating factor, was higher in serum exosomes from young rats, compared with serum exosomes from aged rats. Whereas the prevalence of proinflammatory mediators (C1q [complement component 1q], C3a, and C3b) in serum exosomes increased with age. Microglial expression of C3a/b and C3aR (C3a receptor) increased after serum exosomes from aged rats treatment, compared with serum exosomes from young rats and vehicle groups. Administration of a selective C3aR inhibitor or microglial depletion attenuated synaptic dysfunction associated with serum exosomes from aged rats treatment and improved poststroke functional recovery. Conclusions: Our data suggest that the levels of proinflammatory mediators in serum exosomes increase with age and are associated with worsened stroke outcomes through excessive C3aR-dependent microglial phagoptosis. Modulation of this process may serve as a promising therapy for stroke and other age-related brain disorders.