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)-β-dependent tolerogenic phenotype and promote the expansion of regulatory T cells, whereas no such effects are seen with Atg16l1 deficient CD8α+ 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 CD8α+ 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.

中文翻译：

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CD11b +树突状细胞中的自噬功能受损，会扩大CD4 +调节性T细胞并限制小鼠的动脉粥样硬化。

理性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自噬功能失调在动脉粥样硬化形成过程中起有害作用，从而提示自噬刺激方法可能会带来好处。目的树突状细胞（DC）处于先天性和适应性免疫反应的十字路口，并深刻调节动脉粥样硬化的发展。有趣的是，自噬在动脉粥样硬化过程中在DC功能中的作用以及自噬过程将如何影响疾病发展的问题尚未得到解决。方法和结果 我们表明，在动脉粥样硬化易感的Ldlr-/-（低密度脂蛋白受体缺陷型）小鼠中，自噬通量在脾脏和主动脉DCs中比巨噬细胞高得多，并且在高胆固醇血症条件下被进一步激活。RNA选择性细胞群体的测序和功能研究表明，通过缺失Atg16l1破坏自噬会差异地影响高脂饮食Ldlr-/-小鼠中DC亚群的生物学和功能。Atg16l1缺失的CD11b + DCs会形成TGF（转化生长因子）-β致耐受性表型并促进调节性T细胞的扩增，而Atg16l1缺失的CD8α+ DCs则没有这种作用。DC（所有表达CD11c的细胞）中Atg16l1的缺失会在体内扩大主动脉调节性T细胞，限制了1型T辅助细胞的积累，并减少了Ldlr-/-小鼠的动脉粥样硬化的发展。相反，当在常规CD8α+ DC和CD103 + DC中有选择地删除Atg16l1时，看不到这种效果。总的T细胞或选择性调节性T细胞的消耗消除了Atg16l1缺陷型DC的动脉粥样硬化保护作用。结论与巨噬细胞中的促动脉粥样硬化作用相反，DC的自噬破坏可引起反调节反应，维持高脂饮食下Ldlr-/-小鼠的免疫稳态，并限制动脉粥样硬化的发生。DC中自噬的选择性调节可能构成动脉粥样硬化的一个有趣的治疗靶点。当在传统的CD8α+ DC和CD103 + DC中有选择地删除Atg16l1时，看不到这种效果。总的T细胞或选择性调节性T细胞的消耗消除了Atg16l1缺陷型DC的动脉粥样硬化保护作用。结论与巨噬细胞中的促动脉粥样硬化作用相反，DC的自噬破坏可引起反调节反应，维持高脂饮食下Ldlr-/-小鼠的免疫稳态，并限制动脉粥样硬化的发生。DC中自噬的选择性调节可能构成动脉粥样硬化的一个有趣的治疗靶点。当在传统的CD8α+ DC和CD103 + DC中有选择地删除Atg16l1时，看不到这种效果。总的T细胞或选择性调节性T细胞的消耗消除了Atg16l1缺陷型DC的动脉粥样硬化保护作用。结论与巨噬细胞中的促动脉粥样硬化作用相反，DC的自噬破坏可引起反调节反应，维持高脂饮食下Ldlr-/-小鼠的免疫稳态，并限制动脉粥样硬化的发生。DC中自噬的选择性调节可能构成动脉粥样硬化的一个有趣的治疗靶点。DC的自噬破坏诱导了反调节反应，该反应在高脂饮食下维持Ldlr-/-小鼠的免疫稳态，并限制了动脉粥样硬化的发生。DC中自噬的选择性调节可能构成动脉粥样硬化的一个有趣的治疗靶点。DC的自噬破坏诱导了反调节反应，该反应在高脂饮食下维持Ldlr-/-小鼠的免疫稳态，并限制了动脉粥样硬化的发生。DC中自噬的选择性调节可能构成动脉粥样硬化的一个有趣的治疗靶点。