Metabolic reprogramming of plaque macrophages to resolve inflammation and promote atherosclerotic plaque stability

Atherosclerosis is a chronic inflammatory disease driven by persistent immune activation within the vascular wall. While anti-inflammatory therapies have been shown to reduce cardiovascular events, their non-specific immunosuppressive effects underscore the urgent need for targeted approaches that resolve vascular inflammation without impairing host immunity.

Plaque-resident macrophages exhibit remarkable plasticity and can adopt a spectrum of phenotypes ranging from pro-inflammatory to reparative. Emerging evidence suggests that these phenotypic transitions are strongly influenced by local metabolic cues. Metabolic reprogramming can modulate macrophage function, promoting inflammation resolution and tissue repair. Preliminary data from our lab demonstrates that under low-inflammatory conditions, a subset of macrophages expressing smooth muscle cell (SMC) markers such as ACTA2 emerges within stable plaque regions. These cells display enhanced collagen production and express metabolic enzymes involved in energy metabolism, suggesting a role for energy metabolism in driving a reparative, myofibroblast-like phenotype.

Aim 1: Characterize the metabolic and functional profiles of ACTA2⁺ macrophages in human and mouse atherosclerotic plaques.

Aim 2: Define the role of energy metabolism in promoting macrophage transitions toward collagen-producing, inflammation-resolving phenotypes.

This project will identify metabolic pathways that reprogram macrophages toward reparative, collagen-producing phenotypes in atherosclerosis. These pathways will serve as novel targets for inflammation-resolving therapies that stabilise plaques without broad immunosuppression. Findings will inform biomarker discovery for identifying patients with unstable, inflamed plaques.

Metabolic studies, LC-MS, In vitro cell culture, in vivo mouse models, cardiovascular genetics, molecular biology, confocal microscopy and RNA-sequencing.