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

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 therapeutic potential of deleting Unc5b in mice with advanced atherosclerosis. We generated <i>Unc5b</i>^fl/fl<i>Cx3cr1</i>^creERT2/WT mice, which allowed conditional deletion of Un5b (∆<i>Unc5b</i>^MØ) in monocytes and macrophages by tamoxifen injection. After inducing advanced atherosclerosis by hepatic PCSK9 overexpression and western diet feeding for 20 wk, <i>Unc5b</i> was deleted and hypercholesterolemia was normalized to simulate clinical lipid management. Deletion of myeloid <i>Unc5b</i> led to a 40% decrease in atherosclerotic plaque burden and reduced plaque complexity compared to <i>Unc5b</i>^fl/fl<i>Cx3cr1</i>^WT/WT littermate controls (Ctrl^MØ). Consistently, plaque macrophage content was reduced by 50% in ∆<i>Unc5b</i>^MØ mice due to reduced plaque Ly6C^hi monocyte recruitment and macrophage retention. Compared to Ctrl^MØ mice, plaques in ∆<i>Unc5b</i>^MØ mice had reduced necrotic area and fewer apoptotic cells, which correlated with improved efferocytotic capacity by <i>Unc5b</i>-deficient macrophages in vivo and in vitro. Beneficial changes in macrophage dynamics in the plaque upon <i>Unc5b</i> 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.