INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
J Biol Chem. 2011 Sep 2;286(35):30926-30936. doi: 10.1074/jbc.M111.264325. Epub 2011 Jul 8.
Cholesterol-laden monocyte-derived macrophages are phagocytic cells characteristic of early and advanced atherosclerotic lesions. Interleukin-6 (IL-6) is a macrophage secretory product that is abundantly expressed in atherosclerotic plaques but whose precise role in atherogenesis is unclear. The capacity of macrophages to clear apoptotic cells, through the efferocytosis mechanism, as well as to reduce cellular cholesterol accumulation contributes to prevent plaque progression and instability. By virtue of its capacity to promote cellular cholesterol efflux from phagocyte-macrophages, ABCA1 was reported to reduce atherosclerosis. We demonstrated that lipid loading in human macrophages was accompanied by a strong increase of IL-6 secretion. Interestingly, IL-6 markedly induced ABCA1 expression and enhanced ABCA1-mediated cholesterol efflux from human macrophages to apoAI. Stimulation of ABCA1-mediated cholesterol efflux by IL-6 was, however, abolished by selective inhibition of the Jak-2/Stat3 signaling pathway. In addition, we observed that the expression of molecules described to promote efferocytosis, i.e. c-mer proto-oncogene-tyrosine kinase, thrombospondin-1, and transglutaminase 2, was significantly induced in human macrophages upon treatment with IL-6. Consistent with these findings, IL-6 enhanced the capacity of human macrophages to phagocytose apoptotic cells; moreover, we observed that IL-6 stimulates the ABCA1-mediated efflux of cholesterol derived from the ingestion of free cholesterol-loaded apoptotic macrophages. Finally, the treatment of human macrophages with IL-6 led to the establishment of an anti-inflammatory cytokine profile, characterized by an increased secretion of IL-4 and IL-10 together with a decrease of that of IL-1β. Taken together, our results indicate that IL-6 favors the elimination of excess cholesterol in human macrophages and phagocytes by stimulation of ABCA1-mediated cellular free cholesterol efflux and attenuates the macrophage proinflammatory phenotype. Thus, high amounts of IL-6 secreted by lipid laden human macrophages may constitute a protective response from macrophages to prevent accumulation of cytotoxic-free cholesterol. Such a cellular recycling of free cholesterol may contribute to reduce both foam cell formation and the accumulation of apoptotic bodies as well as intraplaque inflammation in atherosclerotic lesions.
富含胆固醇的单核细胞衍生的巨噬细胞是吞噬细胞，其特征是早期和晚期动脉粥样硬化病变。白细胞介素 6（IL-6）是巨噬细胞的一种分泌产物，在动脉粥样斑块中大量表达，但在动脉粥样硬化发生中的确切作用尚不清楚。巨噬细胞通过吞噬作用机制清除凋亡细胞以及减少细胞内胆固醇积累的能力有助于防止斑块进展和不稳定。由于其促进吞噬细胞-巨噬细胞中细胞内胆固醇流出的能力，ABCA1 被报道可减少动脉粥样硬化。我们证明，人巨噬细胞的脂质负荷伴随着 IL-6 分泌的强烈增加。有趣的是，IL-6 显著诱导 ABCA1 的表达，并增强 ABCA1 介导的人巨噬细胞向载脂蛋白 AI 的胆固醇流出。然而，通过选择性抑制 Jak-2/Stat3 信号通路，IL-6 刺激 ABCA1 介导的胆固醇流出被阻断。此外，我们观察到，在 IL-6 处理后，描述促进吞噬作用的分子，即 c-mer 原癌基因酪氨酸激酶、血小板反应蛋白 1 和转谷氨酰胺酶 2 的表达在人巨噬细胞中显著诱导。与这些发现一致，IL-6 增强了人巨噬细胞吞噬凋亡细胞的能力；此外，我们观察到 IL-6 刺激源自摄取载有游离胆固醇的凋亡巨噬细胞的胆固醇的 ABCA1 介导的流出。最后，用 IL-6 处理人巨噬细胞导致建立抗炎细胞因子谱，其特征在于增加分泌 IL-4 和 IL-10 以及降低 IL-1β 的分泌。总之，我们的结果表明，IL-6 通过刺激 ABCA1 介导的细胞内游离胆固醇流出，有利于人巨噬细胞和吞噬细胞中多余胆固醇的消除，并减弱巨噬细胞的促炎表型。因此，富含脂质的人巨噬细胞分泌的大量 IL-6 可能构成巨噬细胞防止积累细胞毒性游离胆固醇的保护性反应。这种游离胆固醇的细胞再循环可能有助于减少泡沫细胞形成和凋亡小体以及动脉粥样硬化病变中斑块内炎症的积累。
