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

ABSTRACT:

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 (¹¹C)-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 ¹⁴C-acetate uptake were determined in brachiocephalic arteries of western diet-fed apoE^-/- mice. The effect of polarizing stimuli on ¹⁴C-acetate uptake was determined by proinflammatory (interferon-γ + lipopolysaccharide) vs inflammation-resolving (interleukin-4) stimulation of murine macrophages and human carotid endarterectomy specimens over 2 days. ¹⁴C-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 ¹⁴C-acetate uptake. ¹⁴C-acetate uptake progressively decreased in proinflammatory macrophages to 25.9 ± 4.5% of baseline (P < .001). A delayed increase in ¹⁴C-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-γ + lipopolysaccharide decreased ¹⁴C-acetate uptake to 66.5 ± 14.5%, while interleukin-4 increased ¹⁴C-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.

SUBMITTER: Demirdelen S 

PROVIDER: S-EPMC8935477 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature