The CXCR3‐LFA1‐ICAM1 Axis Regulates T Cell Cardiotropism and Maladaptive Cardiac Remodeling in Heart Failure

Abstract

Left ventricular (LV) dysfunction and heart failure (HF) are associated in humans and mice with increased circulating chemokines CXCL9 and CXCL10. T cells expressing their receptor, CXCR3, are expanded in the circulation of HF patients as compared to non‐HF, and are associated with disease progression. CXCR3 signaling upon chemokine recognition in T cells results in integrin activation and T cell adhesion to endothelial cells. We recently reported that the integrin ligand ICAM1 is significantly upregulated in the LV endothelium in mice with HF, and that ICAM1−/− mice have decreased LV T cell recruitment and preserved HF. Thus, we hypothesized that chemokine signaling through CXCR3 regulates integrin dependent adhesion to ICAM1 and contributes to T cell recruitment into the LV and HF. We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT mice, and in vitro differentiated effector T cells to evaluate their integrin dependent affinity to ICAM1 in the presence of chemokines under shear flow conditions. CXCL9 and CXCL10 were upregulated in WT mice in response to 2 and 4 weeks TAC as compared to Sham, correlating with ICAM1, IL‐6 and IL‐1β upregulation. CXCR3+ lymphocytes were expanded in the mediastinal lymph nodes as early as 1 week post TAC and remained increased 2 and 4 weeks post TAC in WT mice, as compared with Sham. CXCR3+ T cells were recruited to the LV 4 weeks post TAC and expressed higher levels of the integrin LFA1, the main ligand of ICAM1, in contrast to CXCR3‐T cells. Moreover, both CXCL9 and CXCL10 induced adhesion of CXCR3+ T cells to ICAM1 under flow conditions in vitro in an LFA‐1 dependent manner, and CXCL9 effect was greater when compared to CXCL10 induced CXCR3+ T cell adhesion to ICAM1. Our data supports a CXCR3‐LFA1‐ICAM1 axis being involved in T cell mediated pathological cardiac remodeling, representing a novel pathway that could be targeted in non‐ischemic HF.Support or Funding InformationNational Institutes of Health NIH RO1 HL123658 and American Heart Association Grant in Aid‐AHA GIA 13GRNT 14560068