Regulatory Role of Dendritic Cells in Postinfarction Healing and Left Ventricular Remodeling
Regulatory Role of Dendritic Cells in Postinfarction Healing and Left Ventricular Remodeling
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DOI：
10.1161/circulationaha.111.052126
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发表时间：
2012-03-13
期刊：
影响因子：
37.8
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Anzai, Atsushi;Anzai, Toshihisa;Fukuda, Keiichi
背景-炎症和免疫反应是心肌梗死后愈合过程中不可或缺的组成部分。我们以前报道的树突状细胞（DC）浸润在梗死的心脏，但是，准确的贡献DC在梗死后healthy.Methods和Results-Bone骨髓细胞从CD 11 c-白喉毒素受体/绿色荧光蛋白转基因小鼠移植到致命照射野生型受体小鼠。重建骨髓来源的细胞后，受体小鼠用白喉毒素（DC消融）或载体（对照）治疗，并通过左冠状动脉结扎造成心肌梗死。对照组心肌梗死后第7天，表达CD 11b和主要组织相容性复合物II的CD 11 c（+）绿色荧光蛋白阳性DC被募集到心脏中，达到峰值。DC消融7天的小鼠显示左心室功能恶化和重构。与对照组相比，DC消融组心肌梗死后炎性细胞因子（如白细胞介素-1 β、白细胞介素-18和肿瘤坏死因子-α）的表达增强并持续，细胞外基质降解延长（与高水平基质金属蛋白酶-9活性相关），白细胞介素-10表达水平降低和内皮细胞增殖减少。体内分析显示，DC消融的梗死增强了单核细胞/巨噬细胞的募集。在这些细胞中，促炎性Ly 6C（高）单核细胞和F4/80（+）CD 206（-）M1巨噬细胞的显著浸润，相反，与对照组相比，DC消融组中梗死心肌中抗炎Ly 6C（低）单核细胞和F4/80（+）CD 206（+）M2巨噬细胞的募集受损。这些结果表明，DC是一种有效的免疫保护调节剂在梗死后愈合过程中通过其控制单核细胞/巨噬细胞的稳态。（循环。2012;125：1234-1245）。
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-1 beta, interleukin-18, and tumor necrosis factor-alpha, 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. (Circulation. 2012;125:1234-1245.)