Molecular mechanism of activation of human cardiac fibroblasts during Pseudomonas aeruginosa infection
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Date
2025-05
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The Ohio State University
Abstract
Though primarily known and studied for its respiratory consequences, the bacterium Pseudomonas aeruginosa (P.a.) also causes cardiac pathology during infection. A common cause of nosocomial infections, otherwise known as healthcare-associated infections, P.a. infections are especially threatening to susceptible patient populations. Furthermore, they impose significant financial burdens on both healthcare facilities and their patients every year. These factors, in conjunction with the prevalence of cardiac dysfunction and its vast implications for human health highlight the need to investigate the mechanistic processes behind the pathological manifestations of P.a. in the heart. Studies from our lab revealed P.a. infection causes severe cardiac inflammation and dysfunction in mice, despite limited bacterial load in the heart. However, the underlying mechanism is unknown. We hypothesize that inflammatory mediators and bacterial products released into the bloodstream by infected immune cells during pulmonary P.a. infection activate cardiac fibroblasts, enhancing cytokine and chemokine release and driving cardiac inflammation. To test our hypothesis in vitro, we used human monocyte-derived macrophages (hMDMs) and cardiac fibroblasts (HCFs). We harvested conditioned media (CM) from P.a. infected hMDMs and exposed it to HCFs (P.a. CM). Our data revealed that exposing HCFs to P.a. CM upregulates gene expression of pro-inflammatory cytokines and chemokines involved in immune cell recruitment. To further investigate mechanisms controlling key cytokine/chemokine expression in HCFs, we identified a MAPK-JNK as a driver for the induction of CCL2 in HCF. In conclusion, our data are consistent with the hypothesis that during pulmonary P.a. infection, immune cells recruited to the lungs interact with the bacterium and release inflammatory mediators into the bloodstream. These, along with released pathogen associated molecular patterns (PAMPs) by P.a. bacterium, activate cardiac fibroblasts. This activation enhances the release of pro-inflammatory cytokines and chemokines (such as CCL2), causing recruitment of leukocytes into heart tissue and contributing to severe cardiac inflammation. Ongoing and future studies are needed to dive deeper into the mechanisms of this pathway and show its potential impact in driving cardiac inflammation in vivo.
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Keywords
Cardiac Inflammation, Bacterial Infection, Pseudomonas aeruginosa, Immune Cell Recruitment, Fibroblasts, Cytokines