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 (e.g., 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 (Y-exo) into aged ischemic rats improved short- and long-term functional outcomes after ischemic stroke and reduced synaptic loss. By contract, similar injections of serum exosomes from aged rats (O-exo) 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 Y-exo, compared to O-exo. Whereas the prevalence of pro-inflammatory mediators (C1q, C3a and C3b) in serum exosomes increased with age. Microglial expression of C3a/b and C3aR increased after O-exo treatment, compared with Y-exo and vehicle groups. Administration of a selective C3aR inhibitor or microglial depletion attenuated synaptic dysfunction associated with O-exo treatment and improved post-stroke functional recovery. Conclusions: Our data suggest that the levels of pro-inflammatory 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.