Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions.
Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions.
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DOI：
10.1161/circulationaha.108.793869
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发表时间：
2008-10-28
期刊：
影响因子：
37.8
通讯作者：
Tall AR
中科院分区：
文献类型：
--
作者：
Yvan-Charvet L;Welch C;Pagler TA;Ranalletta M;Lamkanfi M;Han S;Ishibashi M;Li R;Wang N;Tall AR
两种巨噬细胞ABC转运蛋白ABCA 1和ABCG 1在促进胆固醇从巨噬细胞流出中起主要作用。缺乏ABCA 1和/或ABCG 1的腹膜巨噬细胞显示炎性和趋化因子基因的表达增强。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和后果。基础和LPS刺激的巯基乙酸盐诱导的腹腔巨噬细胞显示出增加的炎症基因表达，顺序为Abca 1 −/− Abcg 1 −/−> Abcg 1 −/−> Abca 1 −/−>WT。在TLR 4或MyD 88/TRIF缺陷的巨噬细胞中，增加的炎症基因表达被消除。TLR 4细胞表面浓度在Abca 1 −/− Abcg 1 −/−> Abcg 1 −/−> Abca 1 −/−或WT巨噬细胞中增加。用环糊精治疗转运蛋白缺陷细胞减少，而胆固醇-环糊精加载增加炎症基因表达。Abca 1 −/− Abcg 1-骨髓源性巨噬细胞对TLR 2、3和4配体的炎症基因反应增强。为了评估体内相关性，我们在Abcg 1 −/−骨髓移植的西方饮食喂养的Ldlr缺陷小鼠中注射IP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。结果表明，HDL和apoA-1发挥抗炎作用，促进胆固醇流出通过ABCG 1和ABCA 1，随之衰减信号通过Toll样受体。在对外周炎症刺激的反应中，含有Abcg 1 −/−巨噬细胞的动脉粥样硬化病变经历了炎症“回声”，这表明低HDL受试者斑块不稳定的可能机制。
Two macrophage ABC transporters, ABCA1 and ABCG1 have a major role in promoting cholesterol efflux from macrophages. Peritoneal macrophages deficient in ABCA1 and/or ABCG1 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. Basal and LPS-stimulated thioglycollate-elicited peritoneal macrophages showed increased inflammatory gene expression in the order Abca1−/−Abcg1−/−>Abcg1−/−>Abca1−/−>WT. The increased inflammatory gene expression was abolished in macrophages deficient in TLR4 or MyD88/TRIF. TLR4 cell surface concentration was increased in Abca1−/−Abcg1−/−>Abcg1−/−>Abca1−/− or WT macrophages. Treatment of transporter deficient cells with cyclodextrin reduced, while cholesterol-cyclodextrin loading increased inflammatory gene expression. Abca1−/−Abcg1- bone marrow-derived macrophages showed enhanced inflammatory gene responses to TLR2,3 and 4 ligands. To assess in vivo relevance we injected IP 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. The results suggest that HDL and apoA-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 HDL.