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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 4

CXCR3+CD4+ T cells from mice and humans with cardiac pressure overload express high levels of LFA-1.

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CXCR3+CD4+ T cells from mice and humans with cardiac pressure overload e...
(A and B) Representative flow cytometry plots (A) and quantification (B) of CD4+ T cells isolated from the mLNs of WT mice at the indicated times after Sham and TAC surgery, indicating surface CXCR3 and LFA-1 expression within the CD4+ gate. Relative values to Sham 1 week (w) are indicated. n = 3 Sham, 3 TAC 1w; 4 Sham, 4 TAC 2w; 3 Sham, 4 TAC 4w. Error bars represent mean ± SEM (*P < 0.05, **P < 0.01, ***P < 0.001; 1-way ANOVA with Bonferroni post hoc test). (C–F) Histogram representation (C and E) and quantification (D and F) of LFA-1 expression on CXCR3+CD4+ and CXCR3–CD4+ T cells in the mLNs of WT mice 4 weeks after TAC surgery (C and D) and in peripheral blood of nonischemic HF patients (E and F). n = 7 TAC mice, 20 nonischemic HF patients. Error bars represent mean ± SEM (*P < 0.05, **P < 0.01, ***P < 0.001; Mann-Whitney unpaired U test).

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