Intravascular adhesion and recruitment of neutrophils in response to CXCL1 depends on their TRPC6 channels
Intravascular adhesion and recruitment of neutrophils in response to CXCL1 depends on their TRPC6 channels
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DOI：
10.1007/s00109-020-01872-4
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发表时间：
2020-01-16
影响因子：
4.7
通讯作者：
Schwab, Albrecht
中科院分区：
文献类型：
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作者：
Lindemann, Otto;Rossaint, Jan;Schwab, Albrecht
在这里，我们报道了TRPC6，瞬时受体电位(TRPC)通道家族的成员，在CXCL1依赖的小鼠中性粒细胞募集中的一个新的作用。中性粒细胞是先天免疫系统的核心成分，它从血液中招募中性粒细胞到炎症部位。募集过程遵循一系列明确的事件，包括与血管壁的粘连、迁移和趋化作用，以到达炎症焦点。潜在信号通路的一个共同特征是利用钙离子作为细胞内的第二信使。然而，所需的钙离子内流通道尚未完全确定。我们使用WT和TRPC6(-/-)中性粒细胞进行体外实验，使用TRPC6(-/-)嵌合小鼠(具有WT或TRPC6(-/-)骨髓细胞的WT小鼠)进行体内研究。在肾缺血和再灌注损伤后，TRPC6(-/-)嵌合小鼠的中性粒细胞募集减少，从血浆肌酐浓度的降低判断为更好的结果。在Cremaster模型中，在含有TRPC6(-/-)中性粒细胞的嵌合小鼠中，CXCL1诱导的中性粒细胞黏附、停滞和移行也减少。利用原子力显微镜和微流控技术，我们可以将TRPC6(-/-)中性粒细胞的募集缺陷归因于通道对内皮细胞黏附的影响。在机制上，TRPC6(-/-)中性粒细胞在最初的黏附过程中表现出较低的钙瞬变，导致RAP1和β(2)整合素的激活减弱，从而减少了ICAM-1的结合。综上所述，我们的研究表明，中性粒细胞中的TRPC6通道是中性粒细胞从血流中招募CXCL1的关键信号模块。
Here we report a novel role for TRPC6, a member of the transient receptor potential (TRPC) channel family, in the CXCL1-dependent recruitment of murine neutrophil granulocytes. Representing a central element of the innate immune system, neutrophils are recruited from the blood stream to a site of inflammation. The recruitment process follows a well-defined sequence of events including adhesion to the blood vessel walls, migration, and chemotaxis to reach the inflammatory focus. A common feature of the underlying signaling pathways is the utilization of Ca2+ ions as intracellular second messengers. However, the required Ca2+ influx channels are not yet fully characterized. We used WT and TRPC6(-/-) neutrophils for in vitro and TRPC6(-/-) chimeric mice (WT mice with WT or TRPC6(-/-) bone marrow cells) for in vivo studies. After renal ischemia and reperfusion injury, TRPC6(-/-) chimeric mice had an attenuated TRPC6(-/-) neutrophil recruitment and a better outcome as judged from the reduced increase in the plasma creatinine concentration. In the cremaster model CXCL1-induced neutrophil adhesion, arrest and transmigration were also decreased in chimeric mice with TRPC6(-/-) neutrophils. Using atomic force microscopy and microfluidics, we could attribute the recruitment defect of TRPC6(-/-) neutrophils to the impact of the channel on adhesion to endothelial cells. Mechanistically, TRPC6(-/-) neutrophils exhibited lower Ca2+ transients during the initial adhesion leading to diminished Rap1 and beta(2) integrin activation and thereby reduced ICAM-1 binding. In summary, our study reveals that TRPC6 channels in neutrophils are crucial signaling modules in their recruitment from the blood stream in response to CXCL1.