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Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation
Immunity ( IF 25.5 ) Pub Date : 2018-01-16 , DOI: 10.1016/j.immuni.2017.11.026
Michael S. Schappe , Kalina Szteyn , Marta E. Stremska , Suresh K. Mendu , Taylor K. Downs , Philip V. Seegren , Michelle A. Mahoney , Sumeet Dixit , Julia K. Krupa , Eric J. Stipes , Jason S. Rogers , Samantha E. Adamson , Norbert Leitinger , Bimal N. Desai

Toll-like receptors (TLRs) sense pathogen-associated molecular patterns to activate the production of inflammatory mediators. TLR4 recognizes lipopolysaccharide (LPS) and drives the secretion of inflammatory cytokines, often contributing to sepsis. We report that transient receptor potential melastatin-like 7 (TRPM7), a non-selective but Ca2+-conducting ion channel, mediates the cytosolic Ca2+ elevations essential for LPS-induced macrophage activation. LPS triggered TRPM7-dependent Ca2+ elevations essential for TLR4 endocytosis and the subsequent activation of the transcription factor IRF3. In a parallel pathway, the Ca2+ signaling initiated by TRPM7 was also essential for the nuclear translocation of NFκB. Consequently, TRPM7-deficient macrophages exhibited major deficits in the LPS-induced transcriptional programs in that they failed to produce IL-1β and other key pro-inflammatory cytokines. In accord with these defects, mice with myeloid-specific deletion of Trpm7 are protected from LPS-induced peritonitis. Our study highlights the importance of Ca2+ signaling in macrophage activation and identifies the ion channel TRPM7 as a central component of TLR4 signaling.



中文翻译:

Chanzyme TRPM7介导脂多糖诱导的Toll样受体4内吞作用和巨噬细胞激活所必需的Ca 2+内流。

Toll样受体(TLR)感知与病原体相关的分子模式,以激活炎症介质的产生。TLR4识别脂多糖(LPS)并驱动炎性细胞因子的分泌,通常促成败血症。我们报告瞬态受体电位褪黑素样7(TRPM7),非选择性但Ca 2+传导离子通道,介导LPS诱导巨噬细胞激活所必需的胞质Ca 2+升高。LPS触发了TLR4内吞作用和随后转录因子IRF3激活所必需的TRPM7依赖性Ca 2+升高。在平行途径中,Ca 2+TRPM7启动的信号转导对于NFκB的核转位也是必不可少的。因此,TRPM7缺陷型巨噬细胞在LPS诱导的转录程序中表现出主要缺陷,因为它们不能产生IL-1β和其他关键促炎细胞因子。与这些缺陷一致,保护了具有Trpm7髓样特异性缺失的小鼠免受LPS诱导的腹膜炎的侵害。我们的研究强调了Ca 2+信号在巨噬细胞激活中的重要性,并确定离子通道TRPM7是TLR4信号的主要成分。

更新日期:2018-01-16
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