Divergence of acetate uptake in proinflammatory and inflammation-resolving macrophages: implications for imaging atherosclerosis

Background Metabolic divergence of macrophages polarized into different phenotypes represents a mechanistically relevant target for non-invasive characterization of atherosclerotic plaques using positron emission tomography (PET). Carbon-11 (C-11)-labeled acetate is a clinically available tracer which accumulates in atherosclerotic plaques, but its biological and clinical correlates in atherosclerosis are undefined. Methods and results Histological correlates of C-14-acetate uptake were determined in brachiocephalic arteries of western diet-fed apoE(-/-) mice. The effect of polarizing stimuli on C-14-acetate uptake was determined by proinflammatory (interferon-gamma + lipopolysaccharide) vs inflammation-resolving (interleukin-4) stimulation of murine macrophages and human carotid endarterectomy specimens over 2 days. C-14-acetate accumulated in atherosclerotic regions of arteries. CD68-positive monocytes/macrophages vs smooth muscle actin-positive smooth muscle cells were the dominant cells in regions with high vs low C-14-acetate uptake. C-14-acetate uptake progressively decreased in proinflammatory macrophages to 25.9 +/- 4.5% of baseline (P < .001). A delayed increase in C-14-acetate uptake was induced in inflammation-resolving macrophages, reaching to 164.1 +/- 21.4% (P < .01) of baseline. Consistently, stimulation of endarterectomy specimens with interferon-gamma + lipopolysaccharide decreased C-14-acetate uptake to 66.5 +/- 14.5%, while interleukin-4 increased C-14-acetate uptake to 151.5 +/- 25.8% compared to non-stimulated plaques (P < .05). Conclusions Acetate uptake by macrophages diverges upon proinflammatory and inflammation-resolving stimulation, which may be exploited for immunometabolic characterization of atherosclerosis.

Automated summary

The study revealed that acetate uptake by macrophages diverges upon proinflammatory and inflammation-resolving stimulation, which may be exploited for immunometabolic characterization of atherosclerosis.