Flt3 Signaling-Dependent Dendritic Cells Protect against Atherosclerosis
Flt3 Signaling-Dependent Dendritic Cells Protect against Atherosclerosis
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DOI：
10.1016/j.immuni.2011.09.014
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发表时间：
2011-11-23
期刊：
影响因子：
32.4
通讯作者：
Steinman, Ralph M.
中科院分区：
文献类型：
--
作者：
Choi, Jae-Hoon;Cheong, Cheolho;Steinman, Ralph M.
动脉粥样硬化的早期事件发生在主动脉内膜，涉及单核细胞变成巨噬细胞。我们在稳定状态的成年小鼠主动脉中寻找这些细胞，令人惊讶的是，我们在内膜中发现了树突状细胞（DCs）的优势。与主动脉外巨噬细胞相比，CD11c(+)MHC IIhi dc吞噬能力差，但具有免疫刺激作用。dc主要有两种类型：经典的Flt3-Flt3L信号依赖性CD103(+)CD11b(-) dc和巨噬细胞集落刺激因子（M-CSF）依赖性CD14(+)CD11b(+)DC-SIGN（+）单核细胞来源的dc。这两种类型在动脉粥样硬化期间都会扩张。通过将Flt3（-/-）与Ldlr（-/-）动脉粥样硬化易感小鼠杂交，我们发现了典型CD103（+）主动脉dc的选择性和显著缺乏症，它们与动脉粥样硬化加剧有关，但血脂没有改变。同时，Flt3(-/-) Ldlr（-/-）小鼠主动脉Foxp3(+) Treg细胞减少，炎症细胞因子mrna增加。因此，功能性dc在正常主动脉内膜中占主导地位，与巨噬细胞相比，CD103（+）经典dc与动脉粥样硬化保护有关。
Early events in atherosclerosis occur in the aortic intima and involve monocytes that become macrophages. We looked for these cells in the steady state adult mouse aorta, and surprisingly, we found a dominance of dendritic cells (DCs) in the intima. In contrast to aortic adventitial macrophages, CD11c(+)MHC IIhi DCs were poorly phagocytic but were immune stimulatory. DCs were of two types primarily: classical Flt3-Flt3L signaling-dependent, CD103(+)CD11b(-) DCs and macrophage-colony stimulating factor (M-CSF)-dependent, CD14(+)CD11b(+)DC-SIGN(+) monocyte-derived DCs. Both types expanded during atherosclerosis. By crossing Flt3(-/-) to Ldlr(-/-) atherosclerosis-prone mice, we developed a selective and marked deficiency of classical CD103(+) aortic DCs, and they were associated with exacerbated atherosclerosis without alterations in blood lipids. Concomitantly, the Flt3(-/-) Ldlr(-/-) mice had fewer Foxp3(+) Treg cells and increased inflammatory cytokine mRNAs in the aorta. Therefore, functional DCs are dominant in normal aortic intima and, in contrast to macrophages, CD103(+) classical DCs are associated with atherosclerosis protection.