Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q
Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q
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DOI：
10.1016/j.atherosclerosis.2016.08.019
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发表时间：
2016-10-01
期刊：
影响因子：
5.3
通讯作者：
Fraser, Deborah A.
中科院分区：
文献类型：
--
作者：
Ho, Minh-Minh;Manughian-Peter, Ayla;Fraser, Deborah A.
背景和目标：本研究探讨了先天免疫蛋白C1 q对巨噬细胞摄取致动脉粥样硬化脂蛋白过程中程序性反应的影响。C1 q在动脉粥样硬化中起着双重作用，已知C1 q激活补体可驱动炎症并促进疾病进展。然而，C1 q在使用小鼠模型的早期疾病中具有动脉粥样硬化保护作用。我们以前的研究已经强调了C1 q在摄取靶点（如致动脉粥样硬化脂蛋白）期间使巨噬细胞向M2样抗炎表型极化中的非补体相关作用。本研究旨在探讨其分子机制。研究方法：我们研究了参与巨噬细胞极化的分子信号传导机制，使用无偏的检测人单核细胞衍生的巨噬细胞在C1 q存在或不存在下的氧化或乙酰化低密度脂蛋白的基因表达谱。结果如下：在该筛选中，C1 q调节Janus激酶和信号转导子和转录激活子（JAK-STAT）信号传导、过氧化物酶体增殖物激活受体（PPAR）信号传导和toll样受体（TLR）信号传导中涉及的基因的表达。C1 q还显示出显著抑制JAKSTAT途径激活（最大降低55% +/- 13%，p = 0.044）并增加PPARs的转录激活（最大增加229% +/- 54%，p = 0.0002），与M2样极化反应一致。这些途径在巨噬细胞中由与不同类型的修饰的致动脉粥样硬化脂蛋白结合的C1 q调节，并导致促炎细胞因子IL-6的释放减少。结论：本研究确定了C1 q在早期动脉粥样硬化中发挥有益作用的潜在分子机制。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Background and aims: This study investigated the effect of innate immune protein C1q on macrophage programmed responses during the ingestion of atherogenic lipoproteins. C1q plays a dual role in atherosclerosis where activation of complement by C1q is known to drive inflammation and promote disease progression. However, C1q is atheroprotective in early disease using mouse models. Our previous studies have highlighted a non-complement associated role for C1q in polarizing macrophages towards an M2-like anti-inflammatory phenotype during ingestion of targets such as atherogenic lipoproteins. This study aims to investigate the molecular mechanisms involved. Methods: We investigated the molecular signaling mechanisms involved in macrophage polarization using an unbiased examination of gene expression profiles in human monocyte derived macrophages ingesting oxidized or acetylated low density lipoproteins in the presence or absence of C1q. Results: Expression of genes involved in Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling, peroxisome proliferator activating receptor (PPAR) signaling and toll-like receptor (TLR) signaling were modulated by C1q in this screen. C1q was also shown to significantly suppress JAKSTAT pathway activation (a maximum 55% +/- 13% reduction, p = 0.044) and increase transcriptional activation of PPARs (a maximum 229% +/- 54% increase, p = 0.0002), consistent with an M2-like polarized response. These pathways were regulated in macrophages by C1q bound to different types of modified atherogenic lipoprotein and led to a reduction in the release of pro-inflammatory cytokine IL-6. Conclusions: This study identifies potential molecular mechanisms for the beneficial role C1q plays in early atherosclerosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.