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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 5

CD4+ T cell recruitment to the LV, but not CD4+ T cell activation, is impaired in Cxcr3–/– mice in response to cardiac pressure overload.

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CD4+ T cell recruitment to the LV, but not CD4+ T cell activation, is im...
CD4+ T cells were isolated from the mLN of WT and Cxcr3–/– mice, 4 weeks after Sham and TAC surgeries. (A and B) CD62LloCD44hi effector CD4+ T cells were identified by flow cytometry (A) and quantified (B). (C and D) CD4+ T cells recruited to the LV were identified by IHC (C) and quantified (D) per LV section. n = 4 Sham, 4 TAC WT; 3 Sham, 5 TAC Cxcr3–/–. Scale bars: 100 μm. Error bars represent mean ± SEM (*P < 0.05, **P < 0.01; 1-way ANOVA with Bonferroni post hoc test). (E–H) The indicated gating strategy shown for WT TAC (E) was used to quantify the total cell number per LV of CD4+ T cells (F), CD11b+ myeloid cells (G), and CD11b+MerTK+CCR2+ recruited macrophages (H) by flow cytometry in WT and Cxcr3–/– mice, 4 weeks after Sham and TAC surgeries. n = 3 Sham, 3 TAC WT; 6 TAC Cxcr3–/– mice. Error bars represent mean ± SEM (*P < 0.05, **P < 0.01; 1-way ANOVA with Bonferroni post hoc test). (I–K) mRNA levels in the LV of WT and Cxcr3–/– mice at 4 weeks after surgery was determined by qPCR for Cxcl9 (I), Cxcl10 (J), and Ifng (K). n = 9 Sham, 10 TAC WT; 3 Sham, 5 TAC Cxcr3–/–. Error bars represent mean ± SEM (*P < 0.05, **P < 0.01; 1-way ANOVA with Bonferroni post hoc test).

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