In situ lipid-loading activates peripheral dendritic cell subsets characterized by cellular ROS accumulation but compromises their capacity to prime näve T cells

被引：1

作者：

Christ, Anette ^{[1
,2
,13
]}

Maas, Sanne L. ^{[3
,4
]}

Jin, Han ^{[1
]}

Lu, Chang ^{[1
]}

Legein, Bart ^{[1
]}

Wijnands, Erwin ^{[1
]}

Temmerman, Lieve ^{[1
]}

Otten, Jeroen ^{[1
]}

Isaacs, Aaron ^{[5
]}

Zenke, Martin ^{[6
,7
,8
]}

Stoll, Monika ^{[9
,10
]}

Biessen, Erik A. L. ^{[1
,3
]}

van der Vorst, Emiel P. C. ^{[1
,3
,4
,11
,12
]}

机构：

[1] Maastricht Univ, Cardiovasc Res Inst Maastricht CARIM, Med Ctr, Dept Pathol, Maastricht, Netherlands

[2] Hlth Off Frankfurt Main, Frankfurt Main, Germany

[3] Rhein Westfal TH Aachen, Inst Mol Cardiovasc Res IMCAR, Aachen, Germany

[4] Rhein Westfal TH Aachen, Interdisciplinary Ctr Clin Res IZKF, Aachen, Germany

[5] Maastricht Univ, Cardiovasc Res Inst Maastricht CARIM, Dept Physiol, Maastricht, Netherlands

[6] Rhein Westfal TH Aachen, Med Sch, Dept Cell Biol, Aachen, Germany

[7] Rhein Westfal TH Aachen, Helmholtz Inst Biomed Engn, D-52074 Aachen, Germany

[8] Rhein Westfal TH Aachen, Med Sch, Dept Hematol Oncol & Stem Cell Transplantat, D-52074 Aachen, Germany

[9] Maastricht Univ, Cardiovasc Res Inst Maastricht CARIM, Med Ctr, Dept Biochem, Maastricht, Netherlands

[10] Westfalische Wilhelms Univ, Inst Human Genet, Genet Epidemiol, Munster, Germany

[11] Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent IPEK, Munich, Germany

[12] Pauwelsstr 30, D-52074 Aachen, Germany

[13] Breite Gasse 28, D-60313 Frankfurt Main, Germany

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2024年 / 210卷

关键词：

Hypercholesterolemia; Dendritic cells; ROS accumulation; T cell priming; CHOLESTEROL ACCUMULATION; ATHEROSCLEROTIC LESIONS; MACROPHAGES; HEMATOPOIESIS; NEUTROPHILS; EXPRESSION; RECEPTORS; MONOCYTES; IMMUNITY; PATHWAYS;

D O I：

10.1016/j.freeradbiomed.2023.11.044

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Background and aims: Dendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established.Methods: In this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr-/-) mice on separate DC subsets, their compartmentalization and functionality.Results: While hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell pro-genitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a pro-foundly reduced capacity to stimulate nave CD4+ T cells.Conclusion: Our data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.

引用

页码：406 / 415

页数：10