Abstract 61: Dendritic Cell Regulates Monocyte/Macrophage Polarization and Inflammatory Response After Myocardial Infarction in Mice

Abstract

Inflammation and immune responses are integral components in the healing process after MI. We previously reported dendritic cell (DC) infiltration in the infarcted heart. However, the precise contribution of DC in postinfarction healing is unclear. Bone-marrow (BM) cells from CD11c-diphtheria toxin receptor/GFP transgenic mice were transplanted into lethally irradiated WT recipient mice. After reconstitution of BM-derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and MI was created by left coronary ligation. CD11c + GFP + DCs expressing CD11b and MHC class II were recruited into the heart, peaking on day 7 after MI in control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as IL-1β, IL-18 and tumor necrosis factor-α, prolonged extracellular matrix degradation associated with a high level of MMP9 activity, and diminished expression level of IL-10 and endothelial cell proliferation following MI compared with control group. In vivo and in vitro analyses revealed that DC-ablated infarcts had an enhanced capacity of monocytes/macrophages recruitment. Among these cells, augmented infiltration of proinflammatory Ly6C high monocytes and F4/80 + CD206 - M1 macrophages, and conversely impaired recruitment of anti-inflammatory Ly6C low monocytes and F4/80 + CD206 + M2 macrophages in the infarcted myocardium were identified in DC-ablated group than in control group. To confirm these results, adoptive transfer experiment was performed. BM cells from WT mice were cultured with recombinant mouse GM-CSF for 6 days and CD11c + BMDCs were then positively collected by magnetic sorting. We confirmed that intravenously injected CFSE-labeled BMDCs reached infarcted zone. Adoptive transfer of BMDCs into DC-depleted mice restored LV function and negated the increases of inflammatory Ly6C high monocytes and myocardial MMP-9 activity following MI. In conclusion, dendritic cell is a potent immunoprotective regulator during the postinfarction healing process, via controlling monocyte/macrophage homeostasis.