Remodeling of the Mononuclear Phagocyte Network Underlies Chronic Inflammation and Disease Progression in Heart Failure: Critical Importance of the Cardiosplenic Axis
Rationale: The role of mononuclear phagocytes in chronic heart failure (HF) is unknown.
Objective: To delineate monocyte, macrophage, and dendritic cell (DC) 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 pro-inflammatory CD11b+F4/80+CD2060− macrophages and CD11b+F4/80+Gr-1hi monocytes in the heart and peripheral blood, respectively, and diminished CD11b+F4/80+Gr-1hi monocytes in the spleen, 2) significantly augmented CD11c+B220− classical DCs (cDCs) and CD11c+/lowB220+ plasmacytoid DCs (pDCs) in both the heart and spleen, and increased cDCs and pDCs in peripheral blood and bone marrow, respectively, 3) augmented CD4+ helper and CD8+ cytotoxic T cells in the spleen, and 4) profound splenic remodeling with more 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 LV dilatation, dysfunction, and fibrosis in naïve 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 DCs) promote immune-mediated injurious responses in the failing heart, and retain this memory upon adoptive transfer.
- Received May 4, 2013.
- Revision received October 30, 2013.
- Accepted November 1, 2013.