首页> 美国卫生研究院文献>American Journal of Physiology - Cell Physiology >Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages
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Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages

机译:内质网应激诱导的凋亡减少和TRPC3缺失的M1巨噬细胞中未折叠的蛋白反应受损

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摘要

Endoplasmic reticulum (ER) stress is a prominent mechanism of macrophage apoptosis in advanced atherosclerotic lesions. Recent studies from our laboratory showed that advanced atherosclerotic plaques in Apoe−/− mice with bone marrow deficiency of the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and fewer apoptotic macrophages than animals transplanted with Trpc3+/+ bone marrow. In vitro, proinflammatory M1 but not anti-inflammatory M2 macrophages derived from Trpc3−/−Apoe−/− animals exhibited reduced ER stress-induced apoptosis. However, whether this was due to a specific effect of TRPC3 deficiency on macrophage ER stress signaling remained to be determined. In the present work we used polarized macrophages derived from mice with macrophage-specific deficiency of TRPC3 to examine the expression level of ER stress markers and the activation status of some typical mediators of macrophage apoptosis. We found that the reduced susceptibility of TRPC3-deficient M1 macrophages to ER stress-induced apoptosis correlates with an impaired unfolded protein response (UPR), reduced mitochondrion-dependent apoptosis, and reduced activation of the proapoptotic molecules calmodulin-dependent protein kinase II and signal transducer and activator of transcription 1. Notably, none of these pathways was altered in TRPC3-deficient M2 macrophages. These findings show for the first time an obligatory requirement for a member of the TRPC family of cation channels in ER stress-induced apoptosis in macrophages, underscoring a rather selective role of the TRPC3 channel on mechanisms related to the UPR signaling in M1 macrophages.
机译:内质网应激是晚期动脉粥样硬化病变中巨噬细胞凋亡的重要机制。我们实验室的最新研究表明,具有钙可渗透通道的瞬态受体潜在规范3(TRPC3)的骨髓缺乏的Apoe -/-小鼠中的晚期动脉粥样硬化斑块的特点是坏死面积减少且数​​量减少凋亡的巨噬细胞要比移植Trpc3 + / + 骨髓的动物高。在体外,源自Trpc3 <->-/- Apoe -/-动物的促炎性M1巨噬细胞而不是抗炎性M2巨噬细胞表现出减少的内质网应激诱导的细胞凋亡。然而,这是否是由于TRPC3缺乏对巨噬细胞ER应激信号传导的特定影响尚待确定。在本工作中,我们使用衍生自具有TRPC3巨噬细胞特异性缺陷的小鼠的极化巨噬细胞来检查ER应激标志物的表达水平和某些典型的巨噬细胞凋亡介质的激活状态。我们发现,TRPC3缺陷型M1巨噬细胞对内质网应激诱导的凋亡的敏感性降低与未折叠的蛋白反应(UPR)受损,线粒体依赖性凋亡减少以及促凋亡分子钙调蛋白依赖性蛋白激酶II和信号的激活降低有关。转录的转录和激活因子1.值得注意的是,在TRPC3缺失的M2巨噬细胞中,这些途径均未改变。这些发现首次显示了ER应激诱导的巨噬细胞凋亡中对阳离子通道的TRPC家族成员的强制性要求,强调了TRPC3通道在与M1巨噬细胞中UPR信号传导相关的机制中的相当选择性的作用。

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