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Lipid-associated macrophages transition to an inflammatory state in human atherosclerosis, increasing the risk of cerebrovascular complications

Dib, Lea ; Koneva, Lada A. ; Edsfeldt, Andreas LU ; Zurke, Yasemin Xiomara ; Sun, Jiangming LU orcid ; Nitulescu, Mihaela LU ; Attar, Moustafa ; Lutgens, Esther ; Schmidt, Steffen and Lindholm, Marie W. LU , et al. (2023) In Nature Cardiovascular Research 2(7). p.656-672
Abstract

The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease, is conceptualized as lipid-driven inflammation in which macrophages play a nonredundant role. However, evidence emerging so far from single-cell atlases suggests a dichotomy between lipid-associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining single-cell RNA sequencing (scRNA-seq) of human surgical carotid endarterectomies in a discovery cohort with bulk RNA-seq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging... (More)

The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease, is conceptualized as lipid-driven inflammation in which macrophages play a nonredundant role. However, evidence emerging so far from single-cell atlases suggests a dichotomy between lipid-associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining single-cell RNA sequencing (scRNA-seq) of human surgical carotid endarterectomies in a discovery cohort with bulk RNA-seq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project), we reveal the existence of PLIN2hi/TREM1hi macrophages as a Toll-like receptor (TLR)-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for cardiovascular disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Cardiovascular Research
volume
2
issue
7
pages
656 - 672
publisher
Nature Publishing Group
external identifiers
  • scopus:85164479390
ISSN
2731-0590
DOI
10.1038/s44161-023-00295-x
language
English
LU publication?
yes
additional info
Funding Information: This work was supported by EU H2020 H2020-SC1-2016-2017–TAXINOMISIS (C.M., L.D.), EU PROJECT 797788 STRIKING STREAKS-Marie Sklodowska-Curie Individual European Fellowship (C.M.), EU FP7-HEALTH-F2-2013-602222–Athero-Flux (C.M., S.S., M.W.L.), EU FP7-HEALTH-F2-2013-602114-Athero-B-Cell (C.M., S.S., M.W.L.), the Novo Nordisk Foundation (NNF15CC0018346 and NNF0064142) (C.M., L.D.), the Kennedy Trust for Rheumatology Research (KENN161701, KENN202101 and KENN192004) (C.M., S.N.S., M.A., L.A.K.), the British Heart Foundation (FS/18/63/34184B) (Y.-X.Z., C.M.), Leducq Foundation for Cardiovascular Research (research grant number 22CVD02) (C.M., L.D., E.L., I.G.), Netcare Physicians Partnership Trust (I.C.), Oxford NIHR Biomedical Research Centre (C.M.), the Swedish Society for Medical Research, the Swedish Research Council (I.G., A.E., J.S., M.N.), the Crafoord Foundation, the Swedish Society of Medicine, the Swedish Heart and Lung Foundation (I.G., A.E., J.S., M.N.), the Diabetes Foundation (I.G., A.E., J.S., M.N.), SUS foundations and funds, and Lund University Diabetes Center (Swedish Research Council - Strategic Research Area Exodiab Dnr 2009-1039, Linnaeus grant Dnr 349-2006-23 and the Swedish Foundation for Strategic Research Dnr IRC15-006) (I.G., A.E., J.S., M.N.). We also acknowledge the Knut and Alice Wallenberg Foundation, the Medical Faculty at Lund University and Region Skåne for generous financial support (I.G., A.E., J.S., M.N.). Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
id
5e115992-c042-4cad-a118-6c77a4769730
date added to LUP
2023-08-02 16:20:57
date last changed
2023-08-23 15:46:33
@article{5e115992-c042-4cad-a118-6c77a4769730,
  abstract     = {{<p>The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease, is conceptualized as lipid-driven inflammation in which macrophages play a nonredundant role. However, evidence emerging so far from single-cell atlases suggests a dichotomy between lipid-associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining single-cell RNA sequencing (scRNA-seq) of human surgical carotid endarterectomies in a discovery cohort with bulk RNA-seq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project), we reveal the existence of PLIN2<sup>hi</sup>/TREM1<sup>hi</sup> macrophages as a Toll-like receptor (TLR)-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for cardiovascular disease.</p>}},
  author       = {{Dib, Lea and Koneva, Lada A. and Edsfeldt, Andreas and Zurke, Yasemin Xiomara and Sun, Jiangming and Nitulescu, Mihaela and Attar, Moustafa and Lutgens, Esther and Schmidt, Steffen and Lindholm, Marie W. and Choudhury, Robin P. and Cassimjee, Ismail and Lee, Regent and Handa, Ashok and Goncalves, Isabel and Sansom, Stephen N. and Monaco, Claudia}},
  issn         = {{2731-0590}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{656--672}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cardiovascular Research}},
  title        = {{Lipid-associated macrophages transition to an inflammatory state in human atherosclerosis, increasing the risk of cerebrovascular complications}},
  url          = {{http://dx.doi.org/10.1038/s44161-023-00295-x}},
  doi          = {{10.1038/s44161-023-00295-x}},
  volume       = {{2}},
  year         = {{2023}},
}