Regulatory Role of Dendritic Cells in Postinfarction Healing and Left Ventricular Remodeling

• Published in: Circulation (New York, N.Y.) Vol. 125; no. 10; pp. 1234 - 1245
• Main Authors: ANZAI, Atsushi, ANZAI, Toshihisa, SANO, Motoaki, YOSHIKAWA, Tsutomu, OKADA, Yasunori, KOYASU, Shigeo, OGAWA, Satoshi, FUKUDA, Keiichi, NAGAI, Shigenori, MAEKAWA, Yuichiro, NAITO, Kotaro, KANEKO, Hidehiro, SUGANO, Yasuo, TAKAHASHI, Toshiyuki, ABE, Hitoshi, MOCHIZUKI, Satsuki
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 13.03.2012
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Bone Marrow Transplantation; Cardiology. Vascular system; Cytokines - immunology; Cytokines - metabolism; Dendritic Cells - cytology; Dendritic Cells - immunology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fibrosis; Fundamental and applied biological sciences. Psychology; Green Fluorescent Proteins - genetics; Homeostasis - immunology; Macrophages - cytology; Macrophages - immunology; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction - immunology; Myocardial Infarction - mortality; Myocardial Infarction - physiopathology; Myocarditis - immunology; Myocarditis - mortality; Myocarditis - physiopathology; Myocardium - immunology; Myocardium - metabolism; Myocardium - pathology; Nitric Oxide Synthase Type II - metabolism; Ventricular Function, Left - immunology; Ventricular Remodeling - immunology; Vertebrates: cardiovascular system; Wound Healing - immunology; Myocardial infarction; Heart failure; Dendritic cell; remodeling; Cardiovascular disease; Inflammation; Coronary heart disease; Myocardial disease; Left ventricle; Immune system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.111.052126

Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear. Bone marrow cells from CD11c-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow-derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD11c(+) green fluorescent protein-positive DCs expressing CD11b and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as interleukin-1β, interleukin-18, and tumor necrosis factor-α, prolonged extracellular matrix degradation associated with a high level of matrix metalloproteinase-9 activity, and diminished expression level of interleukin-10 and endothelial cell proliferation after myocardial infarction compared with the control group. In vivo analyses revealed that DC-ablated infarcts had enhanced monocyte/macrophage recruitment. Among these cells, marked 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 the DC-ablated group compared with the control group. These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis.