PMID- 31610723
OWN - NLM
STAT- MEDLINE
DCOM- 20200630
LR  - 20210310
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 125
IP  - 11
DP  - 2019 Nov 8
TI  - Impaired Autophagy in CD11b(+) Dendritic Cells Expands CD4(+) Regulatory T Cells 
      and Limits Atherosclerosis in Mice.
PG  - 1019-1034
LID - 10.1161/CIRCRESAHA.119.315248 [doi]
AB  - 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 CD8alpha(+) 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 CD8alpha(+) 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.
FAU - Clement, Marc
AU  - Clement M
AD  - 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.).
FAU - Raffort, Juliette
AU  - Raffort J
AD  - 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.).
AD  - Universite COte d'Azur, Institut National de la Sante et de la Recherche 
      Medicale, Centre Mediterraneen de Recherche Moleculaire, University Hospital of 
      Nice, France (J.R., F.L.).
FAU - Lareyre, Fabien
AU  - Lareyre F
AD  - 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.).
AD  - Universite COte d'Azur, Institut National de la Sante et de la Recherche 
      Medicale, Centre Mediterraneen de Recherche Moleculaire, University Hospital of 
      Nice, France (J.R., F.L.).
FAU - Tsiantoulas, Dimitrios
AU  - Tsiantoulas D
AD  - 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.).
FAU - Newland, Stephen
AU  - Newland S
AD  - 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.).
FAU - Lu, Yuning
AU  - Lu Y
AD  - 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.).
FAU - Masters, Leanne
AU  - Masters L
AD  - 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.).
FAU - Harrison, James
AU  - Harrison J
AD  - 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.).
FAU - Saveljeva, Svetlana
AU  - Saveljeva S
AD  - Department of Gastroenterology and Hepatology, University of Cambridge, United 
      Kingdom (S.S., A.K.).
FAU - Ma, Marcella K L
AU  - Ma MKL
AD  - MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research 
      Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Genomics and 
      Transcriptomics Core, Addenbrooke's Hospital, Cambridge, United Kingdom 
      (M.K.L.M., B.Y.H.L., G.S.H.Y.).
FAU - Ozsvar-Kozma, Maria
AU  - Ozsvar-Kozma M
AD  - 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).
FAU - Lam, Brian Y H
AU  - Lam BYH
AD  - MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research 
      Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Genomics and 
      Transcriptomics Core, Addenbrooke's Hospital, Cambridge, United Kingdom 
      (M.K.L.M., B.Y.H.L., G.S.H.Y.).
FAU - Yeo, Giles S H
AU  - Yeo GSH
AD  - MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research 
      Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Genomics and 
      Transcriptomics Core, Addenbrooke's Hospital, Cambridge, United Kingdom 
      (M.K.L.M., B.Y.H.L., G.S.H.Y.).
FAU - Binder, Christoph J
AU  - Binder CJ
AD  - 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).
FAU - Kaser, Arthur
AU  - Kaser A
AD  - Department of Gastroenterology and Hepatology, University of Cambridge, United 
      Kingdom (S.S., A.K.).
FAU - Mallat, Ziad
AU  - Mallat Z
AD  - 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.).
AD  - Institut National de la Sante et de la Recherche Medicale, Paris Cardiovascular 
      Research Center, France (Z.M.).
LA  - eng
GR  - MC_UU_00014/5/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_00014/1/MRC_/Medical Research Council/United Kingdom
GR  - RG/15/11/31593/BHF_/British Heart Foundation/United Kingdom
GR  - MC_UU_12012/1/MRC_/Medical Research Council/United Kingdom
GR  - 106260/Z/14/Z/WT_/Wellcome Trust/United Kingdom
GR  - MC_UU_12012/5/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191015
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Atg16l1 protein, mouse)
RN  - 0 (Atg5 protein, mouse)
RN  - 0 (Autophagy-Related Protein 5)
RN  - 0 (Autophagy-Related Proteins)
RN  - 0 (CD11 Antigens)
RN  - 0 (CD11b Antigen)
RN  - 0 (Clec9a protein, mouse)
RN  - 0 (Itgam protein, mouse)
RN  - 0 (Itgax protein, mouse)
RN  - 0 (Lectins, C-Type)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Receptors, LDL)
SB  - IM
MH  - Animals
MH  - Aorta/*immunology/metabolism/pathology
MH  - Aortic Diseases/immunology/metabolism/pathology/*prevention & control
MH  - Atherosclerosis/immunology/metabolism/pathology/*prevention & control
MH  - *Autophagy
MH  - Autophagy-Related Protein 5/metabolism
MH  - Autophagy-Related Proteins/genetics/metabolism
MH  - Bone Marrow Transplantation
MH  - CD11 Antigens/genetics/metabolism
MH  - CD11b Antigen/*immunology/metabolism
MH  - *Cell Communication
MH  - *Cell Proliferation
MH  - Cells, Cultured
MH  - Dendritic Cells/*immunology/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Lectins, C-Type/genetics/metabolism
MH  - *Lymphocyte Activation
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Plaque, Atherosclerotic
MH  - Receptors, Immunologic/genetics/metabolism
MH  - Receptors, LDL/genetics/metabolism
MH  - Signal Transduction
MH  - T-Lymphocytes, Regulatory/*immunology/metabolism
PMC - PMC6844650
OTO - NOTNLM
OT  - atherosclerosis
OT  - autophagy
OT  - dendritic cells
OT  - immune system
OT  - macrophages
EDAT- 2019/10/16 06:00
MHDA- 2020/07/01 06:00
PMCR- 2019/11/11
CRDT- 2019/10/16 06:00
PHST- 2019/10/16 06:00 [pubmed]
PHST- 2020/07/01 06:00 [medline]
PHST- 2019/10/16 06:00 [entrez]
PHST- 2019/11/11 00:00 [pmc-release]
AID - 10.1161/CIRCRESAHA.119.315248 [doi]
PST - ppublish
SO  - Circ Res. 2019 Nov 8;125(11):1019-1034. doi: 10.1161/CIRCRESAHA.119.315248. Epub 
      2019 Oct 15.