PMID- 38061606
OWN - NLM
STAT- MEDLINE
DCOM- 20231222
LR  - 20240219
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 210
DP  - 2024 Jan
TI  - In situ lipid-loading activates peripheral dendritic cell subsets characterized 
      by cellular ROS accumulation but compromises their capacity to prime naive T 
      cells.
PG  - 406-415
LID - S0891-5849(23)01145-0 [pii]
LID - 10.1016/j.freeradbiomed.2023.11.044 [doi]
AB  - 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 progenitor 
      (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 profoundly reduced 
      capacity to stimulate naive 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.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Christ, Anette
AU  - Christ A
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands; Health Office 
      Frankfurt/Main, Frankfurt/Main, Germany. Electronic address: 
      anette.christ@stadt-frankfurt.de.
FAU - Maas, Sanne L
AU  - Maas SL
AD  - Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 
      Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH 
      Aachen University, Aachen, Germany.
FAU - Jin, Han
AU  - Jin H
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands.
FAU - Lu, Chang
AU  - Lu C
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands.
FAU - Legein, Bart
AU  - Legein B
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands.
FAU - Wijnands, Erwin
AU  - Wijnands E
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands.
FAU - Temmerman, Lieve
AU  - Temmerman L
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands.
FAU - Otten, Jeroen
AU  - Otten J
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands.
FAU - Isaacs, Aaron
AU  - Isaacs A
AD  - Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University, Maastricht, Netherlands.
FAU - Zenke, Martin
AU  - Zenke M
AD  - Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen 
      University Medical School, Aachen, Germany; Helmholtz-Institute for Biomedical 
      Engineering, RWTH Aachen University, 52074, Aachen, Germany; Department of 
      Hematology, Oncology and Stem Cell Transplantation, RWTH Aachen University 
      Medical School, 52074, Aachen, Germany.
FAU - Stoll, Monika
AU  - Stoll M
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands; Genetic 
      Epidemiology, Institute for Human Genetics, Westfalische Wilhelms-University, 
      Munster, Germany.
FAU - Biessen, Erik A L
AU  - Biessen EAL
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands; Institute for 
      Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, 
      Germany.
FAU - van der Vorst, Emiel P C
AU  - van der Vorst EPC
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Centre, Maastricht, Netherlands; Institute for 
      Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, 
      Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen 
      University, Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), 
      Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: 
      evandervorst@ukaachen.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231205
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Lipids)
SB  - IM
MH  - Mice
MH  - Animals
MH  - T-Lymphocytes
MH  - Reactive Oxygen Species/metabolism
MH  - *Hypercholesterolemia/genetics
MH  - Dendritic Cells
MH  - *Atherosclerosis/metabolism
MH  - Lipids
OTO - NOTNLM
OT  - Dendritic cells
OT  - Hypercholesterolemia
OT  - ROS accumulation
OT  - T cell priming
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/12/08 00:42
MHDA- 2023/12/22 06:42
CRDT- 2023/12/07 19:27
PHST- 2023/11/27 00:00 [received]
PHST- 2023/11/30 00:00 [accepted]
PHST- 2023/12/22 06:42 [medline]
PHST- 2023/12/08 00:42 [pubmed]
PHST- 2023/12/07 19:27 [entrez]
AID - S0891-5849(23)01145-0 [pii]
AID - 10.1016/j.freeradbiomed.2023.11.044 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2024 Jan;210:406-415. doi: 
      10.1016/j.freeradbiomed.2023.11.044. Epub 2023 Dec 5.