Impaired Autophagy in CD11b + Dendritic Cells Expands CD4 + Regulatory T Cells and Limits Atherosclerosis in Mice
Open accessAbstract
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. Atg16 l1 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.
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CD11b+ DCs with dysfunctional autophagy due to Atg16l1 deficiency expand aortic CD4+ Treg cells and inhibit atherogenesis in Ldlr−/− mice.
“CD11b+ DCs with dysfunctional autophagy due to Atg16l1 deficiency expand aortic CD4+ Treg cells and inhibit atherogenesis in Ldlr−/− mice [162].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [162]
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Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases
Song, P., An, J., & Zou, M.-H. (2020) · Cells · doi:10.3390/cells9030671 · Cited by 198 · see citing works
- Authors
- Clement, M., Raffort, J., Lareyre, F., Tsiantoulas, D., Newland, S., Lu, Y., Masters, L., Harrison, J., Saveljeva, S., Ma, M. K. L., Ozsvar-Kozma, M., Lam, B. Y. H., Yeo, G. S. H., Binder, C. J., Kaser, A., & Mallat, Z.
- Affiliations
- From the Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom (M.C., J.R., F.L., D.T., S.N., Y.L., L.M., J.H., Z.M.)
- Inserm (FR)
- University of Cambridge (GB)
- Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences Vienna, Austria (M.O.-K., C.J.B)
- Austrian Academy of Sciences (AT)
- Corresponding author
- Mallat, Ziad
- ORCID
- Venue
- Circulation Research
- Published
- 2019-11-08
- Volume
- 125
- Issue
- 11
- Pages
- 1019-1034
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC6844650
- OpenAlex
- W2980818051
- Cited by
- 44
- References
- 41
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2022: 12 · 2021: 12 · 2020: 6
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Circulation Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (106260/Z/14/Z)
- Francis Crick Institute
- British Heart Foundation (CH/10/001/27642, RG/15/11/31593)
- Medical Research Council (MC_UU_00014/5, MC_UU_00014/1, MC_PC_12012)
- H2020 European Research Council (648889)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- autophagy, dendritic cells, CD11b+ dendritic cells, CD4+ regulatory T cells, atherosclerosis, ATG16L1, Ldlr-deficient mice, hypercholesterolemia, TGF-beta, CD8α+ dendritic cells, CD103+ dendritic cells, Th1 cells, immune homeostasis, atheroprotection
- MeSH terms
- Autophagy-Related Proteins, Autophagy-Related Protein 5, Animals, Aorta, Aortic Diseases, Autophagy, Cell Communication, Cells, Cultured, Dendritic Cells, Disease Models, Animal, Female, Lymphocyte Activation, Mice, Inbred C57BL, Receptors, Immunologic, Receptors, LDL, Signal Transduction, Bone Marrow Transplantation, Mice, Knockout, CD11 Antigens, Lectins, C-Type, CD11b Antigen, Cell Proliferation, Atherosclerosis, T-Lymphocytes, Regulatory, Plaque, Atherosclerotic
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