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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1468969
This article is part of the Research Topic Advances and Challenges in Autoimmune Myocarditis and Other Inflammatory Cardiomyopathies: Implications for Diagnosis and Treatment View all articles

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

Provisionally accepted
Danielle J. Beetler Danielle J. Beetler 1Presley Giresi Presley Giresi 1Damian N. Di Florio Damian N. Di Florio 1Jessica J. Fliess Jessica J. Fliess 1Elizabeth J. McCabe Elizabeth J. McCabe 1Molly M. Watkins Molly M. Watkins 1Vivian Xu Vivian Xu 1Matthew E. Auda Matthew E. Auda 1Katelyn A. Bruno Katelyn A. Bruno 2Emily Whelan Emily Whelan 1Stephen P. Kocsis Stephen P. Kocsis 1Brandy H. Edenfield Brandy H. Edenfield 1Sierra A. Walker Sierra A. Walker 1Logan P. Macomb Logan P. Macomb 1Kevin C. Keegan Kevin C. Keegan 1Angita Jain Angita Jain 1Andrea C. Morales-Lara Andrea C. Morales-Lara 1Isha Chekuri Isha Chekuri 1Anneliese R. Hill Anneliese R. Hill 1Houssam Farres Houssam Farres 1Joy Wolfram Joy Wolfram 3Atta Behfar Atta Behfar 4Paul G. Stalboerger Paul G. Stalboerger 4Andre Terzic Andre Terzic 4Leslie Cooper Leslie Cooper 1DeLisa Fairweather DeLisa Fairweather 1*
  • 1 Mayo Clinic Florida, Jacksonville, United States
  • 2 University of Florida, Gainesville, Florida, United States
  • 3 The University of Queensland, Brisbane, Queensland, Australia
  • 4 Mayo Clinic, Rochester, Minnesota, United States

The final, formatted version of the article will be published soon.

    Extracellular 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. PEV, 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. We 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. These differences in EV content corresponded to the differing anti-inflammatory effects of the two types of EVs on viral myocarditis.

    Keywords: Coxsackievirus B3, innate immunity, complement, TLR4, sex differences, microRNA

    Received: 22 Jul 2024; Accepted: 18 Oct 2024.

    Copyright: © 2024 Beetler, Giresi, Di Florio, Fliess, McCabe, Watkins, Xu, Auda, Bruno, Whelan, Kocsis, Edenfield, Walker, Macomb, Keegan, Jain, Morales-Lara, Chekuri, Hill, Farres, Wolfram, Behfar, Stalboerger, Terzic, Cooper and Fairweather. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: DeLisa Fairweather, Mayo Clinic Florida, Jacksonville, United States

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