Remodeling of the Mononuclear Phagocyte Network Underlies Chronic Inflammation and Disease Progression in Heart Failure

Abstract

Rationale The role of mononuclear phagocytes in chronic heart failure (HF) is unknown. Objective Our aim was to delineate monocyte, macrophage, and dendritic cell trafficking in HF and define the contribution of the spleen to cardiac remodeling. Methods and Results We evaluated C57Bl/6 mice with chronic HF 8 weeks after coronary ligation. As compared with sham-operated controls, HF mice exhibited: (1) increased proinflammatory CD11b+F4/80+CD206− macrophages and CD11b+F4/80+Gr-1hi monocytes in the heart and peripheral blood, respectively, and reduced CD11b+F4/80+Gr-1hi monocytes in the spleen; (2) significantly increased CD11c+B220− classical dendritic cells and CD11c+/lowB220+ plasmacytoid dendritic cells in both the heart and spleen, and increased classic dendritic cells and plasmacytoid dendritic cells in peripheral blood and bone marrow, respectively; (3) increased CD4+ helper and CD8+ cytotoxic T-cells in the spleen; and (4) profound splenic remodeling with abundant white pulp follicles, markedly increased size of the marginal zone and germinal centers, and increased expression of alarmins. Splenectomy in mice with established HF reversed pathological cardiac remodeling and inflammation. Splenocytes adoptively transferred from mice with HF, but not from sham-operated mice, homed to the heart and induced long-term left ventricular dilatation, dysfunction, and fibrosis in naive recipients. Recipient mice also exhibited monocyte activation and splenic remodeling similar to HF mice. Conclusions Activation of mononuclear phagocytes is central to the progression of cardiac remodeling in HF, and heightened antigen processing in the spleen plays a critical role in this process. Splenocytes (presumably splenic monocytes and dendritic cells) promote immune-mediated injurious responses in the failing heart and retain this memory on adoptive transfer.

Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose

“…Because the immune system plays an important role not only in infarct healing but also in adverse remodeling and progression of heart failure,20, 21 we evaluated the myocardial content of immune cells with CD45 staining (Figure 5A). The number of CD45 POS cells in the risk and noninfarcted regions was quantitated and expressed as a percent of total cells counted in the corresponding region (Figure 5B).…”

Monocytes and macrophages in cardiac injury and repair

“…Recently, the involvement of monocytes/macrophages in the development and progression of ischemic cardiomyopathy was described (3,50). It was reported that macrophages gradually expand within the remote myocardium during the course of heart failure, while macrophage numbers within the scar wane ( Figure 1C) (3).…”

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…Finally, since apo A-I induces regulatory T cells (Wilhelm et al 2010), which protect against the pro-inflammatory status of endothelial cells , an induction in regulatory T cells following apo A-I transfer may also partly account for the reduced cardiac inflammation in diabetic rats. Since inflammation triggers fibrosis (Ismahil et al 2013;Savvatis et al 2012;Westermann et al 2011), the less pronounced diabetes-induced cardiac fibrosis (cfr. infra) following apo A-I transfer might partly be explained by the decrease in cardiac inflammation.…”