Impaired Autophagy in CD11b+ Dendritic Cells Expands CD4+ Regulatory T Cells And Limits Atherosclerosis in Mice.
Ma, Marcella Kl
Binder, Christoph J
Wolters Kluwer Health
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Clément, M., Raffort, J., Lareyre, F., Tsiantoulas, D., Newland, S., Lu, Y., Masters, L., et al. (2019). Impaired Autophagy in CD11b+ Dendritic Cells Expands CD4+ Regulatory T Cells And Limits Atherosclerosis in Mice.. Circulation Research, 125 1019-1034. https://doi.org/10.1161/CIRCRESAHA.119.315248
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 low-density lipoprotein receptor deficient (Ldlr-/-) mice is substantially higher in splenic and aortic DCs compared to 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-beta-dependent tolerogenic phenotype and promote the expansion of regulatory T cells (Tregs), whereas no such effects are seen with Atg16l1 deficient CD8alpha+ DCs. Atg16l1 deletion in DCs (all CD11c-expressing cells) expands aortic Tregs in vivo, limits the accumulation of T helper cells type 1 (Th1), and reduces the development of atherosclerosis in Ldlr-/- mice. In contrast, no such effects are seen when Atg16l1 is deleted selectively in conventional CD8alpha+ DCs and CD103+ DCs. Total T cell or selective Treg cell depletion abrogates the atheroprotective effect of Atg16l1 deficient DCs. Conclusions: In contrast to its pro-atherogenic 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.
This study was supported by the British Heart Foundation (CH/10/001/27642 and Grant No. 1659), and the European HEALTH 2013.1.3-3 programme
British Heart Foundation (RG/15/11/31593)
WELLCOME TRUST (106260/Z/14/Z)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (648889)
British Heart Foundation (CH/10/001/27642)
External DOI: https://doi.org/10.1161/CIRCRESAHA.119.315248
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298260
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/