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

• Published in: Journal of nuclear cardiology Vol. 29; no. 3; pp. 1266 - 1276
• Main Authors: Demirdelen, Selim, Mannes, Philip Z., Aral, Ali Mubin, Haddad, Joseph, Leers, Steven A., Gomez, Delphine, Tavakoli, Sina
• Format: Journal Article
• Language: English
• Published: Cham Elsevier Inc 01-06-2022; Springer International Publishing; Springer Nature B.V
• Subjects: Acetate; Acetates - metabolism; Animals; Atherosclerosis; Atherosclerosis - diagnostic imaging; Atherosclerosis - metabolism; Cardiology; Cytokines; Humans; Imaging; Inflammation; Inflammation - diagnostic imaging; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Lipopolysaccharides; macrophage polarization; Macrophages - metabolism; Macrophages - pathology; Medicine; Medicine & Public Health; metabolism; Mice; Nuclear Medicine; Original Article; Plaque, Atherosclerotic - diagnostic imaging; Plaque, Atherosclerotic - pathology; Radiology; Smooth muscle; Tomography, X-Ray Computed; atherosclerosis; IFN-γ; NOS2; IL-4; macrophage polarization; metabolism; Acetate; 18F-FDG; IL-1β; imaging; PET; LPS
• ISSN: 1071-3581; 1532-6551
• DOI: 10.1007/s12350-020-02479-5

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.
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).
Acetate uptake by macrophages diverges upon proinflammatory and inflammation-resolving stimulation, which may be exploited for immunometabolic characterization of atherosclerosis.