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Influenza hijacks circulating myeloid cells to inflict Type-I Interferon-fueled damage in the heart

ABSTRACT: Infections by influenza A viruses remain a threat to human health. Although much of the virus’s pathogenesis is confined to the lung, there is evidence that IAV inflames and damages other organs, including the heart. Our understanding of how this occurs, however, is lacking. Here, we identify a hijacked heart-lung axis, whereby influenza infects a relatively minor and ontologically unusual monocyte which preferentially migrates to the heart, differentiates into a cardiac macrophage, and disseminate the virus exclusively to cardiomyocytes, which then support active viral replication. The arrival of influenza in the heart initiates TLR3-dependent IFN-I production by myeloid cells, which signal through the IFN-I receptor (IFNAR1) on cardiomyocytes to cause damage and compromise heart function. Therapeutically dampening IFNAR1 on cardiomyocytes or limiting monocyte accumulation protects the heart while allowing for anti-viral immunity in the lung. Our results uncover an axis for intervention to mitigate cardiovascular risk following influenza infection.

ORGANISM(S): Mus musculus Influenza A virus (A/Puerto Rico/8/34/Mount Sinai(H1N1))

PROVIDER: GSE312462 | GEO | 2025/12/22

REPOSITORIES: GEO

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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

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Influenza hijacks circulating myeloid cells to inflict Type-I Interferon-fueled damage in the heart

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