Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
Circ Res. 2012 Nov 9;111(11):1398-409. doi: 10.1161/CIRCRESAHA.112.269043. Epub 2012 Sep 6.
ATP-binding cassette transporter A1 (ABCA1) plays a critical role in eliminating excess free cholesterol from tissues by effluxing cellular free cholesterol and phospholipids to lipid-poor apolipoprotein AI. Macrophage ABCA1 also dampens proinflammatory myeloid differentiation primary-response protein 88-dependent toll-like receptor signaling by reducing cellular membrane free cholesterol and lipid raft content, indicating a role of ABCA1 in innate immunity. However, whether ABCA1 expression has a role in regulating macrophage function in vivo is unknown.
We investigated whether macrophage ABCA1 expression impacts host defense function, including microbial killing and chemotaxis.
Myeloid cell-specific ABCA1 knockout (MSKO) vs wild-type mice were infected with Listeria monocytogenes (Lm) for 36 hours or 72 hours before euthanasia. Lm-induced monocytosis was similar for wild-type and MSKO mice; however, MSKO mice were more resistant to Lm infection, with significantly less body weight loss, less Lm burden in liver and spleen, and less hepatic damage 3 days postinfection. In addition, Lm-infected MSKO mouse livers had: (1) greater monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 expression; (2) more monocyte/macrophage infiltration; (3) less neutral lipid accumulation; and (4) diminished expression of lipogenic genes. MSKO macrophages showed enhanced chemotaxis toward chemokines in vitro and increased migration from peritoneum in response to lipopolysaccharide in vivo. Lm infection of wild-type macrophages markedly reduced expression of ABCA1 protein, as well as other cholesterol export proteins (such as ATP-binding cassette transporter G1 and apolipoprotein E).
Myeloid-specific ABCA1 deletion favors host response to and clearance of Lm. Macrophage Lm infection reduces expression of cholesterol export proteins, suggesting that diminished cholesterol efflux enhances innate immune function of macrophages.
三磷酸腺苷结合盒转运体 A1（ABCA1）通过将细胞内游离胆固醇和磷脂转运到富含脂的载脂蛋白 AI 中，从组织中清除多余的游离胆固醇，从而发挥关键作用。巨噬细胞 ABCA1 还通过降低细胞内膜游离胆固醇和脂筏含量来抑制促炎髓样分化初级反应蛋白 88 依赖性 toll 样受体信号，表明 ABCA1 在先天免疫中发挥作用。然而，ABCA1 表达是否在调节体内巨噬细胞功能尚不清楚。
我们研究了巨噬细胞 ABCA1 表达是否影响宿主防御功能，包括微生物杀伤和趋化作用。
用李斯特菌（Lm）感染骨髓细胞特异性 ABCA1 敲除（MSKO）与野生型（WT）小鼠 36 小时或 72 小时后安乐死。WT 型和 MSKO 型小鼠的 Lm 诱导单核细胞增多症相似；然而，MSKO 型小鼠对 Lm 感染的抵抗力更强，体重减轻、肝脾 Lm 负荷和感染后 3 天肝损伤均显著减少。此外，Lm 感染的 MSKO 型小鼠肝脏具有以下特征：（1）单核细胞趋化蛋白-1 和巨噬细胞炎症蛋白-2 表达增加；（2）单核细胞/巨噬细胞浸润增加；（3）中性脂质积累减少；（4）脂肪生成基因表达减少。MSKO 型巨噬细胞在体外对趋化因子的趋化作用增强，体内对脂多糖的迁移反应增强。Lm 感染 WT 型巨噬细胞显著降低 ABCA1 蛋白和其他胆固醇外排蛋白（如 ATP 结合盒转运蛋白 G1 和载脂蛋白 E）的表达。
骨髓细胞特异性 ABCA1 缺失有利于宿主对 Lm 的反应和清除。巨噬细胞 Lm 感染降低了胆固醇外排蛋白的表达，表明胆固醇外排减少增强了巨噬细胞的先天免疫功能。
