Deciphering Mechanisms of Immune Cell Trafficking to the Heart
The complex syndrome of heart failure is a chronic, progressive condition in which the heart is unable to pump blood sufficiently to meet the body’s needs. Heart failure is currently the leading cause of mortality and hospitalization in the United States and is associated with a very poor prognosis, complicated by inadequate therapeutic interventions. The failing heart is characterized by enlargement of the cardiac muscle cells and excessive fibrosis, termed adverse cardiac remodeling. Heart failure develops as a result of a variety of pathological stimuli, leading to increased pressures generated in the left ventricle of the heart. The participation of the immune system in adverse cardiac remodeling has recently been supported by several reports, from the Alcaide lab and others, demonstrating the infiltration of immune cells into the failing heart.
Jay Ngwenyama, a fourth year graduate student in the Alcaide lab, is investigating the mechanisms by which immune cells, particularly CD4+ T cells, become activated and recruited to the heart to mediate adverse cardiac remodeling. Using patient samples and the well-established mouse model of heart failure induced by transverse aortic constriction (TAC), Jay discovered a rapid and sustained induction of inflammatory chemokines, signaling proteins that attract immune cells. In particular, the chemokines CXCL9 and CXCL10, were found to be produced in the heart specifically by cardiac myeloid cells and fibroblasts. Furthermore, CD4+ T cells infiltrating the heart were found to express high levels of CXCR3, the receptor for the CXCL9 and CXCL10 chemokines. This was found to be critical for CD4+ T cell recruitment into the heart that mediates cardiac inflammation associated with heart failure. Thus, Jay’s data demonstrate a novel role for CXCR3 and its ligands in mediating CD4+ T cell cardiotropism in pressure overload induced heart failure. This invokes the attractive possibility of targeting CXCR3 therapeutically using a small molecule CXCR3 antagonist, a possibility which has been successful in other experimental models of chronic inflammatory diseases.
Having identified the mechanisms of temporal CD4+ T cell recruitment to the heart, Jay is further investigating the location and type of antigenic response generated during heart failure development using CD4+ T cell signaling transgenic mouse models. These results, together with the growing body of literature supporting distinct inflammatory responses in different etiologies of HF, will enhance our global understanding of cardiac inflammation and its impact in adverse cardiac remodeling and cardiac function.
Ngwenyama N, Salvador AM, Velázquez F, Nevers T, Levy A, Aronovitz MJ, Luster AD, Huggins GS, Alcaide P. 2019. CXCR3 regulates CD4+ T cell cardiotropism in pressure overload induced cardiac dysfunction. JCI Insight Epub ahead of print. Abstract
Nevers T, Salvador AM, Velazquez F, Ngwenyama N, Carrillo-Salinas FJ, Aronovitz M, Blanton RM, Alcaide P. 2017. Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure. J Exp Med. 214: 3311-3329. Abstract