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

J Nucl Cardiol. 2022 Jun;29(3):1266-1276. doi: 10.1007/s12350-020-02479-5. Epub 2021 Jan 8.

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.

Keywords: Acetate; atherosclerosis; imaging; macrophage polarization; metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / metabolism
  • Animals
  • Atherosclerosis* / diagnostic imaging
  • Atherosclerosis* / metabolism
  • Humans
  • Inflammation / diagnostic imaging
  • Interferon-gamma / metabolism
  • Interleukin-4 / metabolism
  • Lipopolysaccharides
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Plaque, Atherosclerotic* / diagnostic imaging
  • Plaque, Atherosclerotic* / pathology
  • Tomography, X-Ray Computed

Substances

  • Acetates
  • Lipopolysaccharides
  • Interleukin-4
  • Interferon-gamma