Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling
Atsushi Anzai1, Toshihisa Anzai, Shigenori Nagai
1Division of Cardiology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. anzai@cpnet.med.keio.ac.jp
Insights
Dendritic cells (DCs) are crucial for heart healing after myocardial infarction. Ablating DCs worsens heart function by promoting inflammation and altering immune cell balance.
Area of Science:
- Immunology
- Cardiology
- Regenerative Medicine
Background:
- Inflammation and immune responses are critical for healing after myocardial infarction.
- Dendritic cell (DC) infiltration in the infarcted heart was previously observed, but their exact role remains unclear.
Purpose of the Study:
- To investigate the specific contribution of dendritic cells (DCs) in the healing process following myocardial infarction.
- To elucidate the immunomodulatory role of DCs in the post-infarction cardiac microenvironment.
Main Methods:
- Bone marrow-derived cells from transgenic mice were transplanted into recipient mice.
- Dendritic cells (DCs) were ablated using diphtheria toxin in mice subjected to myocardial infarction.
- Left ventricular function, cardiac remodeling, cytokine expression, extracellular matrix degradation, and immune cell infiltration were analyzed.
Main Results:
- DC ablation led to deteriorated left ventricular function and remodeling post-myocardial infarction.
- DC-ablated hearts exhibited increased inflammatory cytokines (IL-1β, IL-18, TNF-α) and matrix metalloproteinase-9 activity.
- DC ablation resulted in altered monocyte/macrophage populations, favoring pro-inflammatory M1 over anti-inflammatory M2 phenotypes.
Conclusions:
- Dendritic cells (DCs) act as potent immunoprotective regulators in post-myocardial infarction healing.
- DCs control monocyte and macrophage homeostasis, thereby influencing cardiac repair and function.
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.
Methods And 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.
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