1、樹突狀細胞和動脈粥樣硬化Introduction Dendritic cellsAtherosclerosisLocalization of DCs in AtheroscleroticLesionsThe role of DCs in atherosclerosisEffects to other immune cellsFunctions of different DC subsetsEffects on atherosclerotic lesion progression and plasma lipidsAnti-Inflammatory Therapies Introduction

2、Dendritic cells (DCs)Origin：Hemopoietic stem cellFunction：Play the main role in antigenpresentation，initiating antigen-specific adaptive immune responses and maintaining tolerance to self-antigensPremature DCsMature DCsStimulatory DCsRegulatory DCsDimitry A. Chistiakov，Myeloid dendritic cells: Devel

3、opment, functions, and role in atherosclerotic inflammation，Immunobiology 220 (2015) 833844，5 January 2015 Atherosclerosis (As)A chronic inflammatory disease of the vessel wall. Artery-wall thickens as a result of invasion and accumulation of white blood cells (WBCs) (foam cell) and proliferation of

4、 intimal-smooth-muscle cell creating a fibrofatty plaque.Foam cells Fatty streaks PlaqueAtherosclerotic LesionPlaque coreFibrous capShoulderMedia Stable & vulnerable lesionAtilla Yilmaz，Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques，Atherosclerosis 176 (2004) 101

5、110， April 2004Localization of DCs in AtheroscleroticLesions and the AdventitiaDCs can be detected in the arterial intima of healthy young individuals, and increased numbers of DCs are found in atherosclerotic lesionsThe DCs are mainly located in the shoulder and core of the lesion.The majority of D

6、Cs in advanced plaques seems to be activated, as revealed by the expression of costimulatory molecules (eg, CD83 and CD86) and cytokines, and to cluster with T cells.The distribution of DCsVulnerable lesion stable lesion initial lesionRelated to lipid core radioAtilla Yilmaz，Emergence of dendritic c

7、ells in rupture-prone regions of vulnerable carotid plaques，Atherosclerosis 176 (2004) 101110， April 2004The distribution of DCsDC might be involved in the process of plaque destabilization through the activation of T cellsAtilla Yilmaz，Emergence of dendritic cells in rupture-prone regions of vulner

8、able carotid plaques，Atherosclerosis 176 (2004) 101110， April 2004The role of DCs in atherosclerosisMouse modelsLdl-r/ miceApoe/ miceDCs and T-Cell ActivationDC-hBcl-2Ldl-r/ and wtLdl-r/ miceEmmanuel L. Gautier，Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostas

9、is in Atherosclerosis，Circulation.2009;119:2367-2375，May 4, 2009An enhanced DC lifespan leads to elevation in DC immunogenicity and increased T-cell activation with polarization toward a Th1 profile.DCs and Treg Dietel B, Decreased numbers of regulatory Tcellsare associated with human atheroscleroti

10、c lesion vulnerability and inversely correlate with infiltrated maturedendritic cells. Atherosclerosis, Volume 230, Issue 1, September 2013, Pages 9299Maturedendritic cells are associated withdecreased numbers of regulatory Tcells. Human carotid endarterectomy specimens DCs and B-Cell ActivationEmma

11、nuel L. Gautier，Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis，Circulation.2009;119:2367-2375，May 4, 2009DC-hBcl-2Ldl-r/ and wtLdl-r/ miceIncreased level of anti-oxLDL antibodies (proatherogenic).The effect on the level of EO6 IgM idiot

12、ype (atheroprotective) is controversial.DCs and Atherosclerotic Lesion ProgressionEmmanuel L. Gautier，Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis，Circulation.2009;119:2367-2375，May 4, 2009Little effect on lesion progressionDC-hBcl-2L

13、dl-r/ and wtLdl-r/ miceDCs and Plasma LipidsEmmanuel L. Gautier，Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis，Circulation.2009;119:2367-2375，May 4, 2009The lower total cholesterol is due to a reduction in the abundance of VLDL and LDL.

14、DC-hBcl-2Ldl-r/ and wtLdl-r/ miceAtherosclerotic Lesion and Diet DC-hBcl-2Apoe/ and wtApoe/ miceEmmanuel L. Gautier，Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis，Circulation.2009;119:2367-2375，May 4, 2009The Roles of Various DC Subsets

15、 in AtherogenesisAbigail S，Monocyte-Derived Dendritic Cells Upregulate Extracellular Catabolism of Aggregated Low-Density Lipoprotein on Maturation, Leading to Foam Cell Formation，Arteriosclerosis, Thrombosis, and Vascular Biology.2015;35:2092-2103，August 20, 2015C57BL/6 miceMonocyte-derived dendrit

16、ic cells use exophagy to degrade aggregated LDL and become foam cells.Monocyte-independent dendritic cells are unable to clear LDL deposits. Abigail S，Monocyte-Derived Dendritic Cells Upregulate Extracellular Catabolism of Aggregated Low-Density Lipoprotein on Maturation, Leading to Foam Cell Format

17、ion，Arteriosclerosis, Thrombosis, and Vascular Biology.2015;35:2092-2103，August 20, 2015The ingestion of aggregated LDL was unaffected by the increase in cellular free cholesterol levels.The Roles of Various DC Subsets in AtherogenesisAnti-Inflammatory Therapies Anti-Inflammatory TherapiesStatins Th

18、iazolidinedions Sirolimus Further ExperimentThe abundance of circulating DC subsets/precursors may serve as biomarkers of disease. Further characterizing the phenotype and function of distinct DC subsets in atherosclerosis.Enhancing the lipid-lowering potential of DCs could be an interesting approac

19、h to limit hypercholesterolemia and atherosclerosis.Reference Alma Zernecke，Dendritic Cells in Atherosclerosis Evidence in Mice and Humans，Arterioscler Thromb Vasc Biol， December 7, 2016Myron I. Cybulsky，Macrophages and Dendritic Cells Partners in Atherogenesis，December 16, 2015Abigail S，Monocyte-De

20、rived Dendritic Cells Upregulate Extracellular Catabolism of Aggregated Low-Density Lipoprotein on Maturation, Leading to Foam Cell Formation，Arteriosclerosis, Thrombosis, and Vascular Biology.2015;35:2092-2103，August 20, 2015Razi Khan，Novel anti-inflammatory therapies for the treatment of atherosclerosis，Atherosclerosis，June 2015Dimitry A. Chistiakov，Myeloid dendritic cells: Development, functions, and role in atherosclerotic inflammation，Immunobiology 220 (2015) 833844，5, January 2015Dietel B, Decreased numbers of regulatory Tcellsare associated with huma