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

Area of Science:

• Immunology
• Cardiovascular Biology
• Molecular Medicine

Background:

• Atherosclerosis is driven by unresolved lipid inflammation in arterial walls.
• Macrophage dysfunction, including impaired migration and efferocytosis, exacerbates inflammation and plaque growth.
• Netrin-1 signaling, particularly through its receptor Unc5b, promotes macrophage survival and retention in atherosclerotic plaques.

Purpose of the Study:

• To investigate the therapeutic potential of deleting Unc5b in macrophages for treating advanced atherosclerosis.
• To understand the impact of myeloid-specific Unc5b deletion on plaque burden, complexity, and immune cell dynamics.

Main Methods:

• Generated conditional knockout mice (Unc5bfl/flCx3cr1creERT2/WT) for tamoxifen-inducible deletion of Unc5b in monocytes/macrophages (∆Unc5bMØ).
• Induced advanced atherosclerosis via PCSK9 overexpression and Western diet, followed by Unc5b deletion and normalization of hypercholesterolemia.
• Analyzed atherosclerotic plaque burden, complexity, macrophage content, efferocytosis, and T cell populations.

Main Results:

• Myeloid Unc5b deletion reduced atherosclerotic plaque burden by 40% and plaque complexity.
• Plaque macrophage content decreased by 50% due to reduced monocyte recruitment and retention.
• Unc5b deficiency enhanced macrophage efferocytosis in vivo and in vitro, reducing necrotic and apoptotic areas.
• Atheroprotective T cell populations (T-regulatory, Th2) increased upon Unc5b deletion.

Conclusions:

• Unc5b in myeloid cells is a key driver of inflammation and retention in advanced atherosclerosis.
• Targeting Unc5b represents a promising therapeutic strategy to promote plaque regression and resolution of inflammation.
• Conditional deletion of Unc5b induces pro-resolving immune cell restructuring within atherosclerotic plaques.