Abstract 408: The Role of the Chemokine Receptor CXCR3 - Integrin Lymphocyte Function Associated Antigen 1 (LFA1) - Intercellular Adhesion Molecule 1 (ICAM1) Axis in T Lymphocyte Mediated Cardiac Inflammation in Pressure Overload Induced Heart Failure

Abstract

Background: Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans and mice with increased circulating chemokines CXCL9, CXCL10 and CXCL11. Expression of their receptor, CXCR3, in circulating T cells is associated with disease progression in HF patients. We recently published that ICAM1 is significantly upregulated in the LV endothelium and contributes to the progression of HF by regulating T cell recruitment to the LV in a mouse model of pressure overload (PO) induced HF. As CXCR3 can signal to integrins upon chemokine recognition and induce T cell adhesion to endothelial cells under flow conditions in vitro , we hypothesize that chemokine signaling through CXCR3 contributes to LV T cell recruitment and regulates integrin dependent adhesion to ICAM1 in PO induced HF. Methods and results: We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM1 -/- mice, cardiac fibroblasts (CFB) isolated from adult C57/BL6 mice, flow cytometry and qPCR in mouse tissues and in cells cultured in vitro . The LV expression of CXCL9, 10 and 11 was 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 and increased CXCR3+ T cell LV infiltration. In vitro , CFB cultured with CXCR3+ T cells or with their culture supernatants, induced CXCL9, 10 and 11, as compared to control media cultured CFB, suggesting CFB are a source of these chemokines under stress. 4 weeks post TAC in WT mice, LV recruited CXCR3+ T cells, as well as mediastinal lymph node and circulating CXCR3+ lymphocytes expressed higher levels of the integrin LFA1, the main ligand of ICAM1, than CXCR3- T cells. The same pattern was observed in systemic CXCR3+ T cells in ICAM1 -/- mice, which, in contrast to WT mice, had reduced LV infiltrated T cells. Conclusion: Our data supports a CXCR3-LFA1-ICAM1 axis being involved in non- ischemic HF. Further studies will determine the CXCR3 ligands triggering T cell LFA1 activation through CXCR3 and whether this mechanism regulates the pathology of non- ischemic HF via ICAM-1 mediated adhesion.