TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis.
TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis.
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TRPV4机械敏感离子通道调节脂多糖刺激的巨噬细胞吞噬作用。
DOI：
10.4049/jimmunol.1501688
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Olman MA
中科院分区：
文献类型：
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作者：
Scheraga RG;Abraham S;Niese KA;Southern BD;Grove LM;Hite RD;McDonald C;Hamilton TA;Olman MA
巨噬细胞对颗粒和病原体的吞噬作用是先天宿主防御的重要方面。吞噬功能需要细胞骨架重排，这取决于巨噬细胞表面受体、颗粒/病原体和细胞外基质之间的相互作用。在本报告中，我们确定了机械敏感离子通道、瞬时受体电位香草酸 4 (TRPV4) 在整合脂多糖 (LPS) 和基质硬度信号以控制巨噬细胞表型变化以促进宿主防御和解决肺损伤方面的作用。我们证明活性 TRPV4 介导 LPS 刺激的小鼠巨噬细胞对体外非调理颗粒（大肠杆菌）的吞噬作用以及体外和体内完整小鼠体内调理颗粒（IgG 包被的乳胶珠）的吞噬作用。有趣的是，在发炎或纤维化的肺部中观察到的基质硬度需要使 TRPV4 通道敏感，以介导 LPS 诱导的巨噬细胞吞噬作用的增加。此外，TRPV4 是 LPS 诱导抗炎/促消退细胞因子所必需的。这些发现表明，由细胞外基质硬度变化触发的 TRPV4 信号与 LPS 诱导的信号协同调节巨噬细胞吞噬功能和肺损伤消退。这些机制可能对肺部感染和纤维化背景下巨噬细胞功能的调节很重要。
Macrophage phagocytosis of particles and pathogens is an essential aspect of innate host defense. Phagocytic function requires cytoskeletal rearrangements that depend on the interaction between macrophage surface receptors, particulates/pathogens and the extracellular matrix. In the present report we determine the role of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), in integrating the lipopolysaccharide (LPS) and matrix stiffness signals to control macrophage phenotypic change for host defense and resolution from lung injury. We demonstrate that active TRPV4 mediates LPS-stimulated murine macrophage phagocytosis of non-opsonized particles (E. coli) in vitro and opsonized particles (IgG-coated latex beads) in vitro and in vivo in intact mice. Intriguingly, matrix stiffness in the range seen in inflamed or fibrotic lung is required to sensitize the TRPV4 channel to mediate the LPS-induced increment in macrophage phagocytosis. Furthermore, TRPV4 is required for the LPS induction of anti-inflammatory/pro-resolution cytokines. These findings suggest that signaling through TRPV4, triggered by changes in extracellular matrix stiffness, cooperates with LPS-induced signals to mediate macrophage phagocytic function and lung injury resolution. These mechanisms are likely to be important in regulating macrophage function in the context of pulmonary infection and fibrosis.