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(Circulation. 2008;118:1837-1847.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Increased Inflammatory Gene Expression in ABC Transporter–Deficient Macrophages

Free Cholesterol Accumulation, Increased Signaling via Toll-Like Receptors, and Neutrophil Infiltration of Atherosclerotic Lesions

Laurent Yvan-Charvet, PhD; Carrie Welch, PhD; Tamara A. Pagler, PhD; Mollie Ranalletta, PhD; Mohamed Lamkanfi, PhD; Seongah Han, PhD; Minako Ishibashi, MD, PhD; Rong Li, BS; Nan Wang, PhD; Alan R. Tall, MBBS

From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (L.Y.-C., C.W., T.A.P., M.R., S.H., M.I., R.L., N.W., A.R.T.); and Department of Physiological Chemistry, Genentech, South San Francisco, Calif (M.L.).

Correspondence to Laurent Yvan-Charvet, PhD, Division of Molecular Medicine, Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032. E-mail ly2159{at}columbia.edu

Received May 22, 2008; accepted August 27, 2008.

Background— Two macrophage ABC transporters, ABCA1 and ABCG1, have a major role in promoting cholesterol efflux from macrophages. Peritoneal macrophages deficient in ABCA1, ABCG1, or both show enhanced expression of inflammatory and chemokine genes. This study was undertaken to elucidate the mechanisms and consequences of enhanced inflammatory gene expression in ABC transporter–deficient macrophages.

Methods and Results— Basal and lipopolysaccharide-stimulated thioglycollate-elicited peritoneal macrophages showed increased inflammatory gene expression in the order Abca1^–/–Abcg1^–/–>Abcg1^–/–>Abca1^–/–>wild-type. The increased inflammatory gene expression was abolished in macrophages deficient in Toll-like receptor 4 (TLR4) or MyD88/TRIF. TLR4 cell surface concentration was increased in Abca1^–/–Abcg1^–/–>Abcg1^–/–> Abca1^–/–> wild-type macrophages. Treatment of transporter-deficient cells with cyclodextrin reduced and cholesterol-cyclodextrin loading increased inflammatory gene expression. Abca1^–/–Abcg1^– bone marrow–derived macrophages showed enhanced inflammatory gene responses to TLR2, TLR3, and TLR4 ligands. To assess in vivo relevance, we injected intraperitoneally thioglycollate in Abcg1^–/– bone marrow–transplanted, Western diet–fed, Ldlr-deficient mice. This resulted in a profound inflammatory infiltrate in the adventitia and necrotic core region of atherosclerotic lesions, consisting primarily of neutrophils.

Conclusions— The results suggest that high-density lipoprotein and apolipoprotein A-1 exert anti-inflammatory effects by promoting cholesterol efflux via ABCG1 and ABCA1 with consequent attenuation of signaling via Toll-like receptors. In response to a peripheral inflammatory stimulus, atherosclerotic lesions containing Abcg1^–/– macrophages experience an inflammatory "echo," suggesting a possible mechanism of plaque destabilization in subjects with low high-density lipoprotein levels.

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