Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression
| Autor: | Emily J. Brown, Matthew Spite, Brian E. Sansbury, Lianne C Shanley, Graeme J. Koelwyn, Martin Schlegel, Ada Weinstock, Milessa Silva Afonso, Juan J. Lafaille, Edward A. Fisher, Karishma Rahman, Daniel Peled, Kathryn J. Moore, Monika Sharma, Emma M Corr, P'ng Loke, Lauren Beckett, Coen van Solingen |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Physiology Mice Knockout ApoE chemical and pharmacologic phenomena Inflammation Diet High-Fat T-Lymphocytes Regulatory Article Antibodies Inflammation resolution Immunity Humans Medicine Macrophage Animals Atherosclerosis regression Aorta Cells Cultured Innate immune system business.industry Macrophages Interleukin-2 Receptor alpha Subunit hemic and immune systems Macrophage Activation Oligonucleotides Antisense Acquired immune system Atherosclerosis Neuropilin-1 Plaque Atherosclerotic Disease Models Animal Receptors LDL Immunology Apolipoprotein B-100 Female medicine.symptom Inflammation Mediators Proprotein Convertase 9 Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circ Res |
| ISSN: | 1524-4571 |
| Popis: | 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 lacked Nrp1 expression, 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. |
| Databáze: | OpenAIRE |
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