Key result
Genetic deletion of CXCR3 in mice subjected to cardiac pressure overload disrupted CD4+ T cell infiltration into the heart, prevented adverse cardiac remodeling, and preserved cardiac function.
Why the study?
Although HF is associated with increased CXCL9 and CXCL10, and Th1 cells drive adverse cardiac remodeling in pressure overload-induced cardiac dysfunction, the role of CXCR3 in cardiac T cell recruitment was not fully established.
Genetic deletion of CXCR3 prevents CD4+ T cell infiltration into the heart, protecting against adverse cardiac remodeling and dysfunction in pressure overload-induced heart failure.
Answers are grounded in this paper and cite their sources.
Supports CXCR3 as therapeutic target in HF; leaves open translation of mouse pressure-overload findings to patients.
Heart failure (HF) is associated in humans and mice with increased circulating levels of CXCL9 and CXCL10, chemokine ligands of the CXCR3 receptor, predominantly expressed on CD4+ Th1 cells. Chemokine engagement of receptors is required for T cell integrin activation and recruitment to sites of inflammation. Th1 cells drive adverse cardiac remodeling in pressure overload-induced cardiac dysfunction, and mice lacking the integrin ligand ICAM-1 show defective T cell recruitment to the heart. Here, we show that CXCR3+ T cells infiltrate the heart in humans and mice with pressure overload-induced cardiac dysfunction. Genetic deletion of CXCR3 disrupts CD4+ T cell heart infiltration and prevents adverse cardiac remodeling. We demonstrate that cardiac fibroblasts and cardiac myeloid cells that include resident and infiltrated macrophages are the source of CXCL9 and CXCL10, which mechanistically promote Th1 cell adhesion to ICAM-1 under shear conditions in a CXCR3-dependent manner. To our knowledge, our findings identify a previously unrecognized role for CXCR3 in Th1 cell recruitment into the heart in pressure overload-induced cardiac dysfunction.
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Ngwenyama et al. (2019) studied Heart failure / pressure overload-induced cardiac dysfunction. Genetic deletion of CXCR3 (Cxcr3-/-) vs. Wild-type (WT) mice was evaluated on Cardiac function (fractional shortening) and adverse cardiac remodeling 4 weeks after transverse aortic constriction (p=<0.05). Genetic deletion of CXCR3 in mice subjected to cardiac pressure overload disrupted CD4+ T cell infiltration into the heart, prevented adverse cardiac remodeling, and preserved cardiac function.
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