衰老导致的丝状肌动蛋白聚合信号受损会降低肺泡巨噬细胞对细菌的吞噬作用。

Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria.

作者信息

Li Zhigang, Jiao Yang, Fan Erica K, Scott Melanie J, Li Yuehua, Li Song, Billiar Timothy R, Wilson Mark A, Shi Xueyin, Fan Jie

机构信息

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.

Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240.

出版信息

J Immunol. 2017 Nov 1;199(9):3176-3186. doi: 10.4049/jimmunol.1700140. Epub 2017 Sep 25.

Abstract

In elderly patients, bacterial infection often causes severe complications and sepsis. Compared to younger patients, older patients are more susceptible to sepsis caused by respiratory infection. Macrophage (Mϕ) phagocytosis of bacteria plays a critical role in the clearance of pathogens and the initiation of immune responses. It has been suggested that Mϕ exhibit age-related functional alterations, including reduced chemotaxis, phagocytosis, antibacterial defense, and the ability to generate reactive oxygen species. However, the mechanisms behind these changes remain unclear. The present study sought to determine changes in bacterial phagocytosis in aging alveolar Mϕ (AMϕ) and the underlying mechanisms. We show that bacteria initiate cytoskeleton remodeling in AMϕ through interaction with macrophage receptor with collagenous structure (MARCO), a bacterial scavenger receptor. This remodeling, in turn, promotes enhanced cell surface expression of MARCO and bacterial phagocytosis. We further demonstrate that Rac1-GTP mediates MARCO signaling and activates actin-related protein-2/3 complex, an F-actin nucleator, thereby inducing F-actin polymerization, filopodia formation, and increased cell surface expression of MARCO, all of which are essential for the execution of bacteria phagocytosis. However, AMϕ isolated from aging mice exhibit suppressed Rac1 mRNA and protein expression, which resulted in decreases in Rac1-GTP levels and actin-related protein-2/3 activation, as well as subsequent attenuation of F-actin polymerization, filopodia formation, and cell surface expression of MARCO. As a result, bacterial phagocytosis in aging AMϕ is decreased. This study highlights a previously unidentified mechanism by which aging impairs Mϕ phagocytosis of bacteria. Targeting these pathways may improve outcomes of bacterial infection in elderly patients.

摘要

在老年患者中,细菌感染常导致严重并发症和败血症。与年轻患者相比,老年患者更容易因呼吸道感染而发生败血症。巨噬细胞(Mϕ)对细菌的吞噬作用在病原体清除和免疫反应启动中起关键作用。有人提出,Mϕ表现出与年龄相关的功能改变,包括趋化性降低、吞噬作用减弱、抗菌防御能力下降以及产生活性氧的能力降低。然而,这些变化背后的机制仍不清楚。本研究旨在确定衰老肺泡巨噬细胞(AMϕ)中细菌吞噬作用的变化及其潜在机制。我们发现细菌通过与具有胶原结构的巨噬细胞受体(MARCO)相互作用,引发AMϕ中的细胞骨架重塑,MARCO是一种细菌清道夫受体。这种重塑反过来又促进了MARCO在细胞表面的表达增强和细菌吞噬作用。我们进一步证明,Rac1-GTP介导MARCO信号传导并激活肌动蛋白相关蛋白2/3复合物,一种F-肌动蛋白成核剂,从而诱导F-肌动蛋白聚合、丝状伪足形成以及MARCO在细胞表面的表达增加,所有这些对于细菌吞噬作用的执行都是必不可少的。然而,从衰老小鼠分离的AMϕ表现出Rac1 mRNA和蛋白表达受到抑制,这导致Rac1-GTP水平降低和肌动蛋白相关蛋白2/3激活减少,以及随后F-肌动蛋白聚合、丝状伪足形成和MARCO在细胞表面表达的减弱。结果,衰老AMϕ中的细菌吞噬作用降低。本研究揭示了一种以前未被识别的机制,衰老通过该机制损害Mϕ对细菌的吞噬作用。针对这些途径可能改善老年患者细菌感染的治疗效果。

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