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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- 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
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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