Tryptase promotes human monocyte-derived macrophage foam cell formation by suppressing LXRalpha activation.
Tryptase promotes human monocyte-derived macrophage foam cell formation by suppressing LXRalpha activation.
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DOI：
10.1016/j.bbalip.2010.01.011
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发表时间：
2010-05
期刊：
影响因子：
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通讯作者：
P. Yeong;Y. Ning;Yali Xu;Xiaobo Li;L. Yin
中科院分区：
文献类型：
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作者：
P. Yeong;Y. Ning;Yali Xu;Xiaobo Li;L. Yin
动脉粥样硬化斑块内积聚的肥大细胞分泌高水平的胰蛋白酶，胰蛋白酶可能通过多种途径参与动脉粥样硬化疾病的发病。然而，胰蛋白酶在巨噬细胞脂质代谢中的作用仍有待明确。在本研究中，我们发现在thp -1衍生的巨噬细胞中添加胰蛋白酶会增加细胞内脂质积累和总胆固醇水平。透射电镜观察到胰蛋白酶促进泡沫细胞的形成。这些作用被肥大细胞胰蛋白酶选择性抑制剂APC366所抑制。胰蛋白酶显著抑制22RHC诱导的LXRα蛋白表达激活，可被SAM-11 （par -2特异性中和抗体）逆转，并降低LXRα、ABCG1、ABCA1和SREBP-1c mRNA水平和ABCG1蛋白水平，这些均被APC366阻断。在thp -1来源的巨噬细胞和原代人单核细胞来源的巨噬细胞中，PAR-2激动剂也通过22RHC刺激激活LXRα、ABCG1蛋白表达和LXRα及其靶基因的mRNA水平。先转染PAR-2 siRNA再经胰蛋白酶处理的原代巨噬细胞中，ABCG1蛋白水平、LXRα和ABCG1 mRNA水平均高于对照siRNA处理的细胞。综上所述，我们的数据阐明了人巨噬细胞PAR-2的表达，并提示胰蛋白酶可能通过PAR-2/LXRα/LXRα靶基因信号通路抑制LXRα活化，从而促进巨噬细胞脂质积累和泡沫细胞形成。本研究对胰蛋白酶在动脉粥样硬化泡沫细胞形成和发病机制中的作用有了新的认识。
Accumulated mast cells in atherosclerotic plaques secrete a high level of tryptase that may participate in the pathogenesis of atherosclerotic disease by diverse pathways. However, the role of tryptase in the lipid metabolism of macrophages remains to be defined. In the present study, we found that the addition of tryptase into THP-1-derived macrophages increased both intracellular lipid accumulation and total cholesterol level. Tryptase promoting foam cell formation was also observed by transmission electron microscope. These effects were resisted by APC366, a selective inhibitor of mast cell tryptase. Tryptase dramatically resisted 22RHC induced activation of LXRα protein expression, which can be reversed by SAM-11 (a PAR-2-specific neutralizing antibody) and reduced LXRα, ABCG1, ABCA1 and SREBP-1c mRNA levels and ABCG1 protein level, which were all blocked by APC366. PAR-2 agonist also redeemed 22RHC stimulation to activate LXRα, ABCG1 protein expression, and mRNA levels of LXRα and its target genes in both THP-1-derived macrophages and primary human monocyte-derived macrophages. In primary macrophages that were first transfected with PAR-2 siRNA and then treated with tryptase, both the ABCG1 protein level and mRNA levels of LXRα and ABCG1 were higher than those in the control siRNA-treated cells. Taken together, our data clarified the PAR-2 expression of human macrophages and suggested that tryptase might promote lipid accumulation in macrophages and foam cell formation by suppressing LXRα activation via PAR-2/LXRα/LXRα target genes signaling pathway. This investigation sheds a new light on the role of tryptase in foam cell formation and pathogenesis of atherosclerosis.