TY - JOUR
T1 - Therapeutic effects of platelet-derived extracellular vesicles on viral myocarditis correlate with biomolecular content
AU - Beetler, Danielle J.
AU - Giresi, Presley
AU - Di Florio, Damian N.
AU - Fliess, Jessica J.
AU - McCabe, Elizabeth J.
AU - Watkins, Molly M.
AU - Xu, Vivian
AU - Auda, Matthew E.
AU - Bruno, Katelyn A.
AU - Whelan, Emily R.
AU - Kocsis, Stephen P.C.
AU - Edenfield, Brandy H.
AU - Walker, Sierra A
AU - Macomb, Logan P.
AU - Keegan, Kevin C.
AU - Jain, Angita
AU - Morales-Lara, Andrea C.
AU - Chekuri, Isha
AU - Hill, Anneliese R.
AU - Farres, Houssam
AU - Wolfram, Joy
AU - Behfar, Atta
AU - Stalboerger, Paul G.
AU - Terzic, Andre
AU - Cooper, Leslie T
AU - Fairweather, De Lisa
N1 - Publisher Copyright:
Copyright © 2025 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.
PY - 2024
Y1 - 2024
N2 - Introduction: 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. Methods: 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. Results: 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. Discussion: These differences in EV content corresponded to the differing anti-inflammatory effects of the two types of EVs on viral myocarditis.
AB - Introduction: 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. Methods: 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. Results: 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. Discussion: These differences in EV content corresponded to the differing anti-inflammatory effects of the two types of EVs on viral myocarditis.
KW - TLR4
KW - complement
KW - coxsackievirus B3
KW - innate immunity
KW - microRNA
KW - sex differences
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U2 - 10.3389/fimmu.2024.1468969
DO - 10.3389/fimmu.2024.1468969
M3 - Article
C2 - 39835120
AN - SCOPUS:85215304273
SN - 1664-3224
VL - 15
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1468969
ER -