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CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction
Njabulo Ngwenyama, … , Gordon S. Huggins, Pilar Alcaide
Njabulo Ngwenyama, … , Gordon S. Huggins, Pilar Alcaide
Published February 19, 2019
Citation Information: JCI Insight. 2019;4(7):e125527. https://doi.org/10.1172/jci.insight.125527.
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Research Article Cardiology Inflammation

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction

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Abstract

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.

Authors

Njabulo Ngwenyama, Ane M. Salvador, Francisco Velázquez, Tania Nevers, Alexander Levy, Mark Aronovitz, Andrew D. Luster, Gordon S. Huggins, Pilar Alcaide

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Figure 7

Cardiac function is preserved in Cxcr3–/– mice subjected to cardiac pressure overload induced by TAC.

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Cardiac function is preserved in Cxcr3–/– mice subjected to cardiac pres...
(A–C) Transthoracic short axis M mode images of the mid LV were acquired by echocardiography (A) of WT and Cxcr3–/– mice, 4 weeks after Sham and TAC surgeries to quantify fractional shortening (B) and ejection fraction (C). n = 5 Sham, 7 TAC WT; 5 Sham, 7 TAC Cxcr3–/– mice. Error bars represent mean ± SEM (***P < 0.001; 1-way ANOVA with Bonferroni post hoc test). (D–F) Intraventricular hemodynamic measurements were acquired by a pressure volume transducer catheter to quantify maximum LV pressure (D), as well as dP/dt max (E) and dP/dt min (F) as parameters of cardiac contractility and relaxation, respectively. n = 3 Sham, 3 TAC WT; 3 Sham, 4 TAC Cxcr3–/–. Error bars represent mean ± SEM (*P < 0.05; 1-way ANOVA with Bonferroni post hoc test).

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