TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration
TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration
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DOI：
10.1038/nm1758
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发表时间：
2008-07-01
期刊：
影响因子：
82.9
通讯作者：
Mori, Yasuo
中科院分区：
文献类型：
--
作者：
Yamamoto, Shinichiro;Shimizu, Shunichi;Mori, Yasuo
活性氧（ROS）诱导趋化因子，负责将炎性细胞募集到损伤或感染部位。在这里，我们表明，质膜Ca（2+）渗透通道TRPM 2控制ROS诱导的单核细胞趋化因子的生产。在人U937单核细胞中，过氧化氢（H（2）O（2））通过TRPM 2引起Ca（2+）内流，激活Ca（2+）依赖性酪氨酸激酶Pyk 2，并通过Ras GT3放大Erk信号。这导致了核因子-κ B的核转位，而核因子-κ B是产生趋化因子白细胞介素-8（CXCL 8）所必需的。在Trpm 2缺陷小鼠的单核细胞中，H2 O2诱导的Ca 2+内流和巨噬细胞炎性蛋白2（CXCL 2）（小鼠CXCL 8功能同源物）的产生受损。在葡聚糖硫酸钠诱导的结肠炎炎症模型中，CXCL 2表达、中性粒细胞浸润和溃疡通过Trpm 2破坏而减弱。因此，TRPM 2 Ca（2+）内流控制ROS诱导的信号级联反应，负责趋化因子的产生，这加剧了炎症。我们提出功能性抑制TRPM 2通道作为治疗炎症性疾病的新的治疗策略。
Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evokes Ca(2+) influx through TRPM2 to activate Ca(2+)-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-kappa B essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H(2)O(2)-induced Ca(2+) influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca(2+) influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.