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ABC转运蛋白缺陷型巨噬细胞中炎症基因表达增加：游离胆固醇积累、通过Toll样受体的信号传导增加以及动脉粥样硬化病变中的中性粒细胞浸润。

Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions.

作者信息

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

机构信息

Division of Molecular Medicine, Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032, USA.

出版信息

Circulation. 2008 Oct 28;118(18):1837-47. doi: 10.1161/CIRCULATIONAHA.108.793869. Epub 2008 Oct 13.

DOI:10.1161/CIRCULATIONAHA.108.793869
PMID:18852364
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2756536/
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.

摘要

背景

两种巨噬细胞ABC转运蛋白ABCA1和ABCG1在促进巨噬细胞胆固醇流出中起主要作用。缺乏ABCA1、ABCG1或两者的腹膜巨噬细胞显示炎症和趋化因子基因表达增强。本研究旨在阐明ABC转运蛋白缺陷型巨噬细胞中炎症基因表达增强的机制及后果。

方法与结果

基础状态及脂多糖刺激的巯基乙酸盐诱导的腹膜巨噬细胞炎症基因表达增加，顺序为Abca1(-/-)Abcg1(-/-)>Abcg1(-/-)>Abca1(-/-)>野生型。在缺乏Toll样受体4（TLR4）或MyD88/TRIF的巨噬细胞中，炎症基因表达增加被消除。TLR4细胞表面浓度在Abca1(-/-)Abcg1(-/-)>Abcg1(-/-)>Abca1(-/-)>野生型巨噬细胞中增加。用环糊精处理转运蛋白缺陷型细胞可降低炎症基因表达，而胆固醇-环糊精负载则增加炎症基因表达。Abca1(-/-)Abcg1(-)骨髓来源的巨噬细胞对TLR2、TLR3和TLR4配体显示出增强的炎症基因反应。为评估体内相关性，我们向接受ABCG1(-/-)骨髓移植、喂食西方饮食的Ldlr缺陷小鼠腹腔注射巯基乙酸盐。这导致动脉粥样硬化病变的外膜和坏死核心区域出现严重的炎症浸润，主要由中性粒细胞组成。

结论

结果表明，高密度脂蛋白和载脂蛋白A-1通过ABCG1和ABCA1促进胆固醇流出，从而减弱Toll样受体信号传导，发挥抗炎作用。对外周炎症刺激的反应中，含有ABCG1(-/-)巨噬细胞的动脉粥样硬化病变会经历炎症“回声”，提示高密度脂蛋白水平低的个体中斑块不稳定的一种可能机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/745a/2756536/881e51f66989/nihms126447f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/745a/2756536/111767e1d568/nihms126447f2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/745a/2756536/cbef5dd22014/nihms126447f4.jpg
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