Circulating Pro-Inflammatory Exosomes Worsen Stroke Outcomes in Aging

Abstract

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.

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis

“…Immunohistochemistry and double immunofluorescent staining were performed on the frozen or paraffin sections by incubation with primary antibodies at 4°C overnight as previously described ( 28 ). The primary antibodies used were as follows: rabbit anti-myelin basic protein (MBP) (Cat# ab40390, Abcam, United States; 1:500), mouse anti-SMI32 (Cat# 801701, Biolegend, United States; 1:1000), goat anti-ionized calcium-binding adaptor molecule 1 (Iba1) (Cat# 011-27991, Wako, United States; 1:300), rabbit anti-CD68 (Cat# ab283654, Abcam, United States; 1:100), mouse anti-CD206 (Cat# sc-58986, Santa Cruz Biotechnologies, United States; 1:50), and mouse anti-MBP (Cat# BF8010, Affinity, United States; 1:100).…”

“…The quantification of immunostaining positive cells in the striatum was also quantified by a researcher blinded to the experiment design. The data were presented as the number of positive cells and percent-stained area per field, respectively ( 28 ).…”

The Neuroprotective Effects of Exosomes Derived from TSG101-Overexpressing Human Neural Stem Cells in a Stroke Model

“…miR-146a-5p reduces microglial-mediated neuroinflammation after ischemic stroke [ 42 ]. The levels of proinflammatory mediators in serum exosomes are associated with worsened stroke outcomes in C3aR-dependent microglial phagoptosis [ 43 ]. The delivery of NGF mRNA and protein via exosomes facilitates the recovery from brain damage by cerebral ischemia [ 44 ].…”

Extracellular vesicles beyond biomarkers: Effectors of antibody-mediated rejection

“…In turn, these pro-inflammatory EVs can contribute to vascular inflammation, hypertension, and rejection. [3][4][5][6][7] The findings by Franzin…”