Science translational medicineDec 10, 2025

Reducing specific immune signals may improve heart inflammation after COVID-19 mRNA vaccination in animal models

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Increased levels of C-X-C motif chemokine ligand 10 (CXCL10) and interferon-γ (IFN-γ) were observed after mRNA vaccination.

Rare cases of noninfective myocarditis have been reported, particularly in young males after the second dose of mRNA vaccines.
Neutralizing CXCL10 and IFN-γ during the second dose reduced vaccine-induced cardiac injury in mouse models.
Cardiac stress markers, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), were decreased with neutralization of these cytokines.
Human induced pluripotent stem cell-derived cardiomyocytes exhibited impaired contractility and increased inflammation when exposed to CXCL10 and IFN-γ.
Genistein treatment reduced cardiac injury markers and inflammatory cell infiltration in mouse models exposed to these cytokines or vaccinated with BNT162b2.

Simplified

Messenger RNA (mRNA) vaccines against SARS-CoV-2 are highly effective and were instrumental in curbing the COVID-19 pandemic. However, rare cases of noninfective myocarditis, particularly in young males and typically after the second dose, have been observed. Here, we explore the mediators of this myocarditis to better understand and to enhance the safety of future mRNA vaccines. Through analysis of human plasma data and in vitro experiments with human macrophages and T cells, we identified increased C-X-C motif chemokine ligand 10 (CXCL10) and interferon-γ (IFN-γ) after exposure to BNT162b2 (Pfizer) or mRNA-1273 (Moderna). Neutralization of CXCL10 and IFN-γ during the second dose (21 days after the first dose) reduced vaccine-induced cardiac injury in mice. Neutralization also reduced cardiac stress markers such as the release of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and expression of inflammatory genes in human induced pluripotent stem cell (iPSC)-derived cardiac spheroids. When exposed to these cytokines in vitro, human iPSC-derived cardiomyocytes (iPSC-CMs) exhibited impaired contractility, arrhythmogenicity, and proinflammatory gene expression patterns. Genistein, a phytoestrogen implicated in reducing cardiovascular inflammation, mitigated these effects in iPSC-CMs. In mice exposed to these cytokines or receiving BNT162b2 vaccination, genistein treatment reduced cardiac injury markers and attenuated infiltration of neutrophils and macrophages into the heart. These findings implicate CXCL10-IFN-γ signaling as a contributor to myocardial injury in experimental models of mRNA vaccination and indicate that pharmacologic modulation, such as with genistein, may mitigate cytokine-driven injury.

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Competing interests

Competing interests: J.C.W. is a cofounder and scientific advisory board member of Greenstone Biosciences. All other authors declare that they have no competing interests.

PubMed

Reducing specific immune signals may improve heart inflammation after COVID-19 mRNA vaccination in animal models

Abstract

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Competing interests

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