Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression
- 26 April 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 127 (3), 335-353
- https://doi.org/10.1161/CIRCRESAHA.119.316461
Abstract
Rationale: Regression of atherosclerosis is an important clinical goal; however, the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, yet the numbers of these immunosuppressive cells decrease with disease progression, and whether they contribute to atherosclerosis regression is not known. Objective: We investigated the roles of Tregs in the resolution of atherosclerotic inflammation, tissue remodeling, and plaque contraction during atherosclerosis regression. Methods and Results: Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. Single-cell RNA-sequencing of plaque immune cells revealed that unlike Tregs from progressing plaques that expressed markers of natural Tregs derived from the thymus, Tregs in regressing plaques lackedNrp1expression, suggesting that they are induced in the periphery during lipid-lowering therapy. To test whether Tregs are required for resolution of atherosclerotic inflammation and plaque regression, Tregs were depleted using CD25 monoclonal antibody in atherosclerotic mice during apolipoprotein B antisense oligonucleotide-mediated lipid lowering. Morphometric analyses revealed that Treg depletion blocked plaque remodeling and contraction, and impaired hallmarks of inflammation resolution, including dampening of the T helper 1 response, alternative activation of macrophages, efferocytosis, and upregulation of specialized proresolving lipid mediators. Conclusions: Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and regression of disease.Funding Information
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL084312)
- HHS | NIH | National Heart, Lung, and Blood Institute (R35HL135799)
- HHS | NIH | National Heart, Lung, and Blood Institute (P01HL131481)
- HHS | NIH | National Heart, Lung, and Blood Institute (P01HL131478)
- HHS | NIH | National Institute of General Medical Sciences (P01GM095467)
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL106173)
- HHS | NIH | National Heart, Lung, and Blood Institute (F32HL136044)
- HHS | NIH | National Heart, Lung, and Blood Institute (T32HL098129)
- U.S. Department of Defense (12019098)
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