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Increased Inflammatory Gene Expression in ABC Transporter-Deficient Macrophages Free Cholesterol Accumulation, Increased Signaling via Toll-Like Receptors, and Neutrophil Infiltration of Atherosclerotic Lesions

(2008) CIRCULATION. 118(18). p.1837-1847
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Abstract
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. (Circulation. 2008; 118: 1837-1847.)
Keywords
NECROSIS-FACTOR-ALPHA, HIGH-DENSITY-LIPOPROTEIN, CELLULAR CHOLESTEROL, LIPID-ACCUMULATION, ABCA1-DEFICIENT MACROPHAGES, INDUCED APOPTOSIS, ABCG1(-/-) BONE-MARROW, APOLIPOPROTEIN-E, MICE, EFFLUX

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Chicago
Yvan-Charvet, L, C Welch, TA Pagler, M Ranalletta, Mohamed Lamkanfi, S Han, M Ishibashi, R Li, N Wang, and AR Tall. 2008. “Increased Inflammatory Gene Expression in ABC Transporter-Deficient Macrophages Free Cholesterol Accumulation, Increased Signaling via Toll-Like Receptors, and Neutrophil Infiltration of Atherosclerotic Lesions.” Circulation 118 (18): 1837–1847.
APA
Yvan-Charvet, L., Welch, C., Pagler, T., Ranalletta, M., Lamkanfi, M., Han, S., Ishibashi, M., et al. (2008). Increased Inflammatory Gene Expression in ABC Transporter-Deficient Macrophages Free Cholesterol Accumulation, Increased Signaling via Toll-Like Receptors, and Neutrophil Infiltration of Atherosclerotic Lesions. CIRCULATION, 118(18), 1837–1847.
Vancouver
1.
Yvan-Charvet L, Welch C, Pagler T, Ranalletta M, Lamkanfi M, Han S, et al. Increased Inflammatory Gene Expression in ABC Transporter-Deficient Macrophages Free Cholesterol Accumulation, Increased Signaling via Toll-Like Receptors, and Neutrophil Infiltration of Atherosclerotic Lesions. CIRCULATION. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS; 2008;118(18):1837–47.
MLA
Yvan-Charvet, L et al. “Increased Inflammatory Gene Expression in ABC Transporter-Deficient Macrophages Free Cholesterol Accumulation, Increased Signaling via Toll-Like Receptors, and Neutrophil Infiltration of Atherosclerotic Lesions.” CIRCULATION 118.18 (2008): 1837–1847. Print.
@article{836708,
  abstract     = {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. (Circulation. 2008; 118: 1837-1847.)},
  author       = {Yvan-Charvet, L and Welch, C and Pagler, TA and Ranalletta, M and Lamkanfi, Mohamed and Han, S and Ishibashi, M and Li, R and Wang, N and Tall, AR},
  issn         = {0009-7322},
  journal      = {CIRCULATION},
  keywords     = {NECROSIS-FACTOR-ALPHA,HIGH-DENSITY-LIPOPROTEIN,CELLULAR CHOLESTEROL,LIPID-ACCUMULATION,ABCA1-DEFICIENT MACROPHAGES,INDUCED APOPTOSIS,ABCG1(-/-) BONE-MARROW,APOLIPOPROTEIN-E,MICE,EFFLUX},
  language     = {eng},
  number       = {18},
  pages        = {1837--1847},
  publisher    = {LIPPINCOTT WILLIAMS & WILKINS},
  title        = {Increased Inflammatory Gene Expression in ABC Transporter-Deficient Macrophages Free Cholesterol Accumulation, Increased Signaling via Toll-Like Receptors, and Neutrophil Infiltration of Atherosclerotic Lesions},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.108.793869},
  volume       = {118},
  year         = {2008},
}

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