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Apolipoprotein E derived from CD11c⁺ cells ameliorates atherosclerosis.

ABSTRACT: Atherosclerosis is studied in models with dysfunctional lipid homeostasis-predominantly the ApoE^-/- mouse. The role of antigen-presenting cells (APCs) for lipid homeostasis is not clear. Using a LacZ reporter mouse, we showed that CD11c⁺ cells were enriched in aortae of ApoE^-/- mice. Systemic long-term depletion of CD11c⁺ cells in ApoE^-/- mice resulted in significantly increased plaque formation associated with reduced serum ApoE levels. In CD11c^cre+ApoE^fl/fl and Albumin^cre+ApoE^fl/fl mice, we could show that ≈70% of ApoE is liver-derived and ≈25% originates from CD11c⁺ cells associated with significantly increased atherosclerotic plaque burden in both strains. Exposure to acLDL promoted cholesterol efflux from CD11c⁺ cells and cell-specific deletion of ApoE resulted in increased inflammation reflected by increased IL-1β serum levels. Our results determined for the first time the level of ApoE originating from CD11c⁺ cells and demonstrated that CD11c⁺ cells ameliorate atherosclerosis by the secretion of ApoE.

SUBMITTER: Sauter M

PROVIDER: S-EPMC8749187 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Apolipoprotein E derived from CD11c+ cells ameliorates atherosclerosis.

Sauter Manuela M Sauter Reinhard J RJ Nording Henry H Lin Chaolan C Olbrich Marcus M Autenrieth Stella S Gleissner Christian C Thunemann Martin M Otero Nadia N Lutgens Esther E Aherrahrou Zouhair Z Wolf Dennis D Zender Lars L Meuth Sven S Feil Robert R Langer Harald F HF

iScience 20211225 1

Atherosclerosis is studied in models with dysfunctional lipid homeostasis-predominantly the ApoE-/- mouse. The role of antigen-presenting cells (APCs) for lipid homeostasis is not clear. Using a LacZ reporter mouse, we showed that CD11c+ cells were enriched in aortae of ApoE-/- mice. Systemic long-term depletion of CD11c+ cells in ApoE-/- mice resulted in significantly increased plaque formation associated with reduced serum ApoE levels. In ...[more]

PMID: 35036868

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Project description:BackgroundThroughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4+ T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B100 (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (TH1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4+ T cells with an atheroprotective, regulatory T cell (Treg) phenotype in healthy individuals. Yet, the function of apoB-reactive Tregs and their relationship with pathogenic TH1 cells remain unknown.MethodsTo interrogate the function of autoreactive CD4+ T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B978-993 (apoB+) at the single-cell level.ResultsWe found that apoB+ T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a Treg-like transcriptome, although only 21% of all apoB+ T cells expressed the Treg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB+ T cells formed several clusters with mixed TH signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of TH1, T helper cell type 2 (TH2), and T helper cell type 17 (TH17), and of follicular-helper T cells. ApoB+ T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic TH1/TH17-like cells with proinflammatory properties and only a residual Treg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed TH1/TH17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB+ Tregs in lineage tracing of hyperlipidemic Apoe-/- mice. In adoptive transfer experiments, converting apoB+ Tregs failed to protect from atherosclerosis.ConclusionsOur results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive Tregs as a novel cellular target in atherosclerosis.

Dataset Information

Apolipoprotein E derived from CD11c⁺ cells ameliorates atherosclerosis.

Publications

Apolipoprotein E derived from CD11c<sup>+</sup> cells ameliorates atherosclerosis.

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