Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis.
Division of Cardiology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. anzai@cpnet.med.keio.ac.jp
Atsushi
A
Anzai
Toshihisa
T
Anzai
Shigenori
S
Nagai
Yuichiro
Y
Maekawa
Kotaro
K
Naito
Hidehiro
H
Kaneko
Yasuo
Y
Sugano
Toshiyuki
T
Takahashi
Hitoshi
H
Abe
Satsuki
S
Mochizuki
Motoaki
M
Sano
Tsutomu
T
Yoshikawa
Yasunori
Y
Okada
Shigeo
S
Koyasu
Satoshi
S
Ogawa
Keiichi
K
Fukuda
D000818:Animals; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005355:Fibrosis; D049452:Green Fluorescent Proteins / Q000235:genetics; D006706:Homeostasis / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology*; D009205:Myocarditis / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016277:Ventricular Function, Left / Q000276:immunology*; D020257:Ventricular Remodeling / Q000276:immunology*; D014945:Wound Healing / Q000276:immunology*
D016207:Cytokines; D049452:Green Fluorescent Proteins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse