Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cardiology Inflammation

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

  • Text
  • PDF
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

×

Figure 6

Cxcr3–/– mice are protected from adverse cardiac remodeling induced by cardiac pressure overload.

Options: View larger image (or click on image) Download as PowerPoint

Cxcr3–/– mice are protected from adverse cardiac remodeling induced by ...
LV tissue sections were isolated from WT and Cxcr3–/– mice, 4 weeks after Sham and TAC surgeries. IHC was used to determine perivascular fibrosis (A) (quantified in C) as well as interstitial fibrosis (B) (quantified in D) by Picrosirius red staining. Scale bars: 100 μm. (E and F) Mean cardiomyocyte area was quantified by wheat germ agglutinin (WGA) IHC of LV tissue sections (E) (as shown in F). n = 4 Sham, 5 TAC WT; 3 Sham, 5 TAC Cxcr3–/– mice. Scale bars: 50 μm. Error bars represent mean ± SEM (*P < 0.05, ***P < 0.001; 1-way ANOVA with Bonferroni post hoc test). (G) The relative LV mRNA expression of the α and β myosin heavy chain isoforms were determined by qPCR to assess pathological cardiomyocyte hypertrophy. n = 3 Sham, 3 TAC WT; 3 Sham, 5 TAC Cxcr3–/– mice. Error bars represent mean ± SEM (*P < 0.05; 1-way ANOVA with Bonferroni post hoc test).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts