Impaired Autophagy in CD11b+ Dendritic Cells Expands CD4+ Regulatory T Cells and Limits Atherosclerosis in Mice
Impaired Autophagy in CD11b+ Dendritic Cells Expands CD4+ Regulatory T Cells and Limits Atherosclerosis in Mice
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DOI：
10.1161/circresaha.119.315248
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发表时间：
2019-11-08
影响因子：
20.1
通讯作者：
Mallat, Ziad
中科院分区：
文献类型：
--
作者：
Clement, Marc;Raffort, Juliette;Mallat, Ziad
原理：动脉粥样硬化是一种慢性炎症性疾病。最近的研究表明，内皮细胞，平滑肌细胞和巨噬细胞中的功能障碍性自噬在动脉粥样硬化形成过程中起着有害的作用，从而表明自噬刺激方法可能提供益处。目的：树突状细胞（Dendritic cells，DCs）是天然免疫和适应性免疫的交叉点，在动脉粥样硬化的发生发展中起重要作用。有趣的是，自噬在动脉粥样硬化过程中DC功能中的作用以及自噬过程如何影响疾病发展尚未得到解决。方法和结果：在这里，我们表明，自噬流量在动脉粥样硬化易感的Ldlr（-/-）（低密度脂蛋白受体缺陷）小鼠的脾脏和主动脉的DCs相比，巨噬细胞，并进一步激活高胆固醇血症条件下。对选择性细胞群的RNA测序和功能研究表明，通过缺失Atg 16 l1破坏自噬对高脂饮食下Ldlr（-/-）小鼠中DC亚群的生物学和功能有不同影响。Atg 16 l1缺陷型CD 11b（+）DCs形成TGF（转化生长因子）-β依赖性致耐受表型，并促进调节性T细胞的扩增，而Atg 16 l1缺陷型CD 8 α（+）DCs没有观察到这种效应。DCs中Atg 16 l1缺失（所有CD 11 c表达细胞）在体内扩增主动脉调节性T细胞，限制1型辅助性T细胞的积累，并减少Ldlr（-/-）小鼠动脉粥样硬化的发展。相反，当Atg 16 l1在常规CD 8 α（+）DCs和CD 103（+）DCs中选择性缺失时，没有观察到这种作用。总T细胞或选择性调节性T细胞消耗消除了Atg 16 l1缺陷DC的动脉粥样硬化保护作用。结论：与其在巨噬细胞中的致动脉粥样硬化作用相反，DC中的自噬破坏诱导了一种反调节反应，该反应在高脂饮食下维持Ldlr（-/-）小鼠的免疫稳态并限制动脉粥样硬化形成。选择性调节树突状细胞自噬可能成为动脉粥样硬化治疗的一个重要靶点。
Rationale: Atherosclerosis is a chronic inflammatory disease. Recent studies have shown that dysfunctional autophagy in endothelial cells, smooth muscle cells, and macrophages, plays a detrimental role during atherogenesis, leading to the suggestion that autophagy-stimulating approaches may provide benefit. Objective: Dendritic cells (DCs) are at the crossroad of innate and adaptive immune responses and profoundly modulate the development of atherosclerosis. Intriguingly, the role of autophagy in DC function during atherosclerosis and how the autophagy process would impact disease development has not been addressed. Methods and Results: Here, we show that the autophagic flux in atherosclerosis-susceptible Ldlr(-/-) (low-density lipoprotein receptor-deficient) mice is substantially higher in splenic and aortic DCs compared with macrophages and is further activated under hypercholesterolemic conditions. RNA sequencing and functional studies on selective cell populations reveal that disruption of autophagy through deletion of Atg16l1 differentially affects the biology and functions of DC subsets in Ldlr(-/-) mice under high-fat diet. Atg16l1 deficient CD11b(+) DCs develop a TGF (transforming growth factor)-beta-dependent tolerogenic phenotype and promote the expansion of regulatory T cells, whereas no such effects are seen with Atg16l1 deficient CD8 alpha(+) DCs. Atg16l1 deletion in DCs (all CD11c-expressing cells) expands aortic regulatory T cells in vivo, limits the accumulation of T helper cells type 1, and reduces the development of atherosclerosis in Ldlr(-/-) mice. In contrast, no such effects are seen when Atg16l1 is deleted selectively in conventional CD8 alpha(+) DCs and CD103(+) DCs. Total T-cell or selective regulatory T-cell depletion abrogates the atheroprotective effect of Atg16l1 deficient DCs. Conclusions: In contrast to its proatherogenic role in macrophages, autophagy disruption in DCs induces a counter-regulatory response that maintains immune homeostasis in Ldlr(-/-) mice under high-fat diet and limits atherogenesis. Selective modulation of autophagy in DCs could constitute an interesting therapeutic target in atherosclerosis.