Targeting Unc5b in macrophages drives atherosclerosis regression and pro- resolving immune cell function

• 成果类型: Article
• 署名作者: Schlegel, Martin; Cyr, Yannick; Newman, Alexandra A. C.; Schreyer, Korbinian; Duran, Jose Gabriel Barcia; Sharma, Monika; Bozal, Fazli K.; Gourvest, Morgane; La Forest, Maxwell; Afonso, Milessa S.; van Solingen, Coen; Fisher, Edward A.; Moore, Kathryn J.
• 署名单位: Technical University of Munich; New York University; New York University; Gilead Sciences
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9052
• DOI: 10.1073/pnas.2412690121
• 发表日期: 2024-10-29
• 关键词: guidance cue netrin-1; regulatory t-cells; receptor unc5b; cardiovascular-disease; plaque regression; m2 macrophages; statin therapy; coronary; retention; inflammation

摘要

Atherosclerosis results from lipid- driven inflammation of the arterial wall that fails to resolve. Imbalances in macrophage accumulation and function, including diminished migratory capacity and defective efferocytosis, fuel maladaptive inflammation and plaque progression. The neuroimmune guidance cue netrin-1 has dichotomous roles in inflammation partly due to its multiple receptors; in atherosclerosis, netrin-1 promotes macrophage survival and retention via its receptor Unc5b. To minimize the pleiotropic effects of targeting netrin-1, we tested the therapeuticpotential of deleting Unc5b in mice with advanced atherosclerosis. We generated Unc5b fl/fl Cx3cr1 creERT2/WT mice, which allowed conditional deletion of Un5b (triangle Unc5bM & Oslash;) in monocytes and macrophages by tamoxifen injection. After inducing advanced atherosclerosis by hepatic PCSK9 overexpression and western diet feeding for 20 wk, Unc5b was deleted and hypercholesterolemia was normalized to simulate clinical lipid management. Deletion of myeloid Unc5b led to a 40% decrease in atherosclerotic plaque burden and reduced plaque complexity compared to Unc5bfl/flCx- 3cr1 WT/WT littermate controls (CtrlM & Oslash;). Consistently, plaque macrophage content was reduced by 50% in triangle Unc5b M & Oslash; mice due to reduced plaque Ly6Chimonocyte recruitment and macrophage retention. Compared to CtrlM & Oslash; mice, plaques in triangle Unc5b M & Oslash; mice had reduced necrotic area and fewer apoptotic cells, which correlated with improved efferocytotic capacity by Unc5b- deficient macrophages in vivo and in vitro. Beneficial changes in macrophage dynamics in the plaque upon Unc5b deletion were accompanied by an increase in atheroprotective T cell populations, including T- regulatory and Th2 cells. Our data identify Unc5b in advanced atherosclerosis as a therapeutic target to induce pro- resolving restructuring of the plaque immune cells and to promote atherosclerosis regression.