Phagocyte and Lymphatics Cross-talk

Background: Previous reports from our group have revealed the importance of clearing apoptotic cardiomyocyte antigen by the process of macrophage efferocytosis, after myocardial infarction (MI). Separately, other significant studies in the heart have revealed an increase in Vegf-C and lymphatic vessels post-cardiac injury. Objective: To determine the potential physiological significance of antigen trafficking to cardiac lymph nodes and whether efferocytes regulate lymphangiogenesis. Methods and Results: Mice transgenic for a cardiac-specific mCherry-reporter revealed significant accumulation of cardiac antigen in mediastinal lymph nodes (mLN), after experimental MI. Specifically, mCherry-positive phagocytes in mLNs were GR1-neg, CD11b-pos, and CCR7-pos. Deficiencies or blockade of macrophage phagocytosis receptors inhibited mononuclear phagocyte accumulation in mLNs. Unexpectedly, absence of scavenger receptor CD36 also blocked MI-induced lymphangiogenesis. To examine molecular signaling mechanisms, primary macrophages were fed apoptotic cells and gene expression of the phagocyte was profiled. Interestingly, macrophages fed dying cells showed inductions of both protein and mRNA expression of VegfC. Conclusions: Our studies suggest that efferocytosis is not only key to clearance of antigen to lymph nodes after MI, but also reprograms phagocytes to secrete lymphangiogenic factors during cardiac wound healing. Current and future studies are examining the pathophysiologic significance of these findings.