AUTHOR=Beetler Danielle J. , Giresi Presley , Di Florio Damian N. , Fliess Jessica J. , McCabe Elizabeth J. , Watkins Molly M. , Xu Vivian , Auda Matthew E. , Bruno Katelyn A. , Whelan Emily R. , Kocsis Stephen P. C. , Edenfield Brandy H. , Walker Sierra A. , Macomb Logan P. , Keegan Kevin C. , Jain Angita , Morales-Lara Andrea C. , Chekuri Isha , Hill Anneliese R. , Farres Houssam , Wolfram Joy , Behfar Atta , Stalboerger Paul G. , Terzic Andre , Cooper Leslie T. , Fairweather DeLisa 

TITLE=Therapeutic effects of platelet-derived extracellular vesicles on viral myocarditis correlate with biomolecular content

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1468969

DOI=10.3389/fimmu.2024.1468969

ISSN=1664-3224

ABSTRACT=IntroductionExtracellular vesicles (EVs) can potently inhibit inflammation yet there is a lack of understanding about the impact of donor characteristics on the efficacy of EVs. The goal of this study was to determine whether the sex and age of donor platelet-derived EVs (PEV) affected their ability to inhibit viral myocarditis.MethodsPEV, isolated from men and women of all ages, was compared to PEV obtained from women under 50 years of age, which we termed premenopausal PEV (pmPEV). Because of the protective effect of estrogen against myocardial inflammation, we hypothesized that pmPEV would be more effective than PEV at inhibiting myocarditis. We injected PEV, pmPEV, or vehicle control in a mouse model of viral myocarditis and examined histology, gene expression, protein profiles, and performed proteome and microRNA (miR) sequencing of EVs.ResultsWe found that both PEV and pmPEV significantly inhibited myocarditis; however, PEV was more effective, which was confirmed by a greater reduction of inflammatory cells and proinflammatory and profibrotic markers determined using gene expression and immunohistochemistry. Proteome and miR sequencing of EVs revealed that PEV miRs specifically targeted antiviral, Toll-like receptor (TLR)4, and inflammasome pathways known to contribute to myocarditis while pmPEV contained general immunoregulatory miRs.DiscussionThese differences in EV content corresponded to the differing anti-inflammatory effects of the two types of EVs on viral myocarditis.