中性粒细胞中Piezo1的表达调节剪切诱导的NETosis-动脉网

Piezo1 expression in neutrophils regulates shear-induced NETosis

Nature 等信源发布 2024-08-22 19:11

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AbstractNeutrophil infiltration and subsequent extracellular trap formation (NETosis) is a contributing factor in sterile inflammation. Furthermore, neutrophil extracellular traps (NETs) are prothrombotic, as they provide a scaffold for platelets and red blood cells to attach to. In circulation, neutrophils are constantly exposed to hemodynamic forces such as shear stress, which in turn regulates many of their biological functions such as crawling and NETosis.

摘要中性粒细胞浸润和随后的细胞外陷阱形成（NETosis）是无菌性炎症的促成因素。此外，嗜中性粒细胞胞外陷阱（NETs）具有促血栓形成作用，因为它们为血小板和红细胞提供了附着的支架。在循环中，嗜中性粒细胞不断暴露于血流动力学力，如剪切应力，从而调节其许多生物学功能，如爬行和NETosis。

However, the mechanisms that mediate mechanotransduction in neutrophils are not fully understood. In this study, we demonstrate that shear stress induces NETosis, dependent on the shear stress level, and increases the sensitivity of neutrophils to NETosis-inducing agents such as adenosine triphosphate and lipopolysaccharides.

然而，介导嗜中性粒细胞机械转导的机制尚不完全清楚。在这项研究中，我们证明剪切应力诱导NETosis，取决于剪切应力水平，并增加中性粒细胞对NETosis诱导剂如三磷酸腺苷和脂多糖的敏感性。

Furthermore, shear stress increases intracellular calcium levels in neutrophils and this process is mediated by the mechanosensitive ion channel Piezo1. Activation of Piezo1 in response to shear stress mediates calpain activity and cytoskeleton remodeling, which consequently induces NETosis. Thus, activation of Piezo1 in response to shear stress leads to a stepwise sequence of cellular events that mediates NETosis and thereby places neutrophils at the centre of localized inflammation and prothrombotic effects..

此外，剪切应力增加了嗜中性粒细胞的细胞内钙水平，这一过程是由机械敏感离子通道Piezo1介导的。响应剪切应力激活Piezo1介导钙蛋白酶活性和细胞骨架重塑，从而诱导NETosis。因此，响应剪切应力激活Piezo1会导致细胞事件的逐步发生，从而介导NETosis，从而将中性粒细胞置于局部炎症和促血栓形成作用的中心。。

IntroductionNeutrophils are the most abundant type of circulating leukocytes. As a central component of the innate immune system, they represent the first line of defence against various microorganisms such as bacteria, fungi, and protozoa1. In addition to their contribution to host defence, neutrophils have also been recognized as important drivers of chronic inflammatory diseases such as autoimmune disorders, cancers, and cardiovascular diseases1,2,3.Neutrophils are mechanosensitive, and hemodynamic shear stress regulates their activation e.g., during inflammation.

引言中性粒细胞是最丰富的循环白细胞类型。作为先天免疫系统的核心组成部分，它们代表了抵抗各种微生物（如细菌，真菌和原生动物）的第一道防线1。除了对宿主防御的贡献外，嗜中性粒细胞还被认为是慢性炎症性疾病的重要驱动因素，如自身免疫性疾病，癌症和心血管疾病1,2,3。嗜中性粒细胞具有机械敏感性，血流动力学剪切应力调节其活化，例如在炎症过程中。

Under static conditions, neutrophils have a spread-out cytoplasmic morphology, can form pseudopods, and migrate on glass slides. Upon exposure to shear stress, they retract their pseudopods and form a rounded morphology4,5. Furthermore, shear stress increases the sensitivity of neutrophils to platelet-activating factor and consequently the shedding of L-selectin into the extracellular space.

在静态条件下，中性粒细胞具有扩散的细胞质形态，可以形成伪足，并在载玻片上迁移。暴露于剪切应力后，它们缩回其伪足并形成圆形形态4,5。此外，剪切应力增加了中性粒细胞对血小板活化因子的敏感性，从而增加了L-选择素向细胞外空间的脱落。

Additionally, shear stress increases the activation of the integrin αMβ2 on neutrophils and modulates neutrophil morphology6.One of the most important characteristics of neutrophils is their ability to release their DNA into the extracellular space, forming so-called neutrophil extracellular traps (NETs).

此外，剪切应力增加了整合素αMβ2在嗜中性粒细胞上的活化，并调节嗜中性粒细胞的形态6。嗜中性粒细胞最重要的特征之一是它们能够将DNA释放到细胞外空间，形成所谓的嗜中性粒细胞胞外陷阱（NETs）。

NETs are web-like chromatin structures decorated with cytosolic and granule proteins7. NETs trap, neutralize, and kill pathogens but, if dysregulated, can contribute to the pathogenesis of immune-related disorders such as cardiovascular diseases, by contributing to the activation of the coagulation pathway8.

NETs是用胞质和颗粒蛋白修饰的网状染色质结构7。NETs捕获，中和和杀死病原体，但如果失调，可能通过促进凝血途径的激活而导致免疫相关疾病（如心血管疾病）的发病机制8。

For example, NETs have been implicated in the pathogenesis of arterial9,10 and venous thrombosis11,12, sepsis13, and autoimmune vasculitis14.The NET release process, known as NETosis, occurs via two main pathways. .

例如，NETs与动脉9,10和静脉血栓形成11,12，败血症13和自身免疫性血管炎14的发病机制有关。NET释放过程称为NETosis，通过两种主要途径发生。

Shear stress stimulation of neutrophils for NET measurement was achieved by resuspending neutrophils in complete RPMI with 10% FBS and recirculation of cells through the µ-Slide 0.1 (ibidi, Australia) for 10 min at flow rates of 50, 250, and 1000 µL/min to induce shear stress levels of 4, 20, and 80 dyne/cm2, respectively.

通过将中性粒细胞重悬于含10%FBS的完全RPMI中并通过μ-Slide 0.1（ibidi，Australia）再循环细胞10分钟，以50250和1000μL/min的流速诱导剪切应力水平分别为4,20和80达因/平方厘米。

The 10 min exposure time is based on our preliminary experiments. Exposure for less than 10 min did not reliably yield a significant response. Conversely, doubling the shear stress exposure time results in the loss of many activated cells due to their adherence to the tubing. The static control group was rested inside a chamber slide for the duration of the shear stress stimulation, under otherwise the same condition.

10分钟的曝光时间是基于我们的初步实验。暴露少于10分钟并不能可靠地产生显着的反应。相反，剪切应力暴露时间加倍会导致许多活化细胞由于粘附在管子上而丢失。在剪切应力刺激期间，静态对照组在相同条件下休息在腔室载玻片内。

To assess the role of extracellular Ca2+ in shear induced NETosis, neutrophils were exposed to shear stress in the presence or absence of 2 mM EGTA in the cell culture media.Followed by that, cells were collected and incubated inside the chamber slide coated with Cell-Tak™ (Cat# CLS354240, Corning, USA) for 3 h to allow them to adhere and form NETs.Shear stress stimulation for the measurement of changes in intracellular calcium levels ([Ca2+]i) in neutrophils was performed using calcium imaging and confocal microscopy.

为了评估细胞外Ca2+在剪切诱导的NETosis中的作用，在细胞培养基中存在或不存在2mM EGTA的情况下，将嗜中性粒细胞暴露于剪切应力。然后，收集细胞并在涂有Cell-Tak TM（Cat#CLS354240，Corning，USA）的室载玻片内孵育3小时，使其粘附并形成网。使用钙成像和共聚焦显微镜进行剪切应力刺激以测量嗜中性粒细胞中细胞内钙水平（[Ca2+]i）的变化。

Isolated neutrophils were seeded inside the µ-Slide 0.1 (ibidi, Australia) precoated with Cell-Tak™ (Cat# CLS354240, Corning, USA) for 15 min to ensure cell adhesion. The neutrophils were then loaded with 2.5 µM Fluo-4 AM (Thermo Fisher Scientific, Australia) at 37 °C in HBSS buffer for 30 min. The µ-Slide channels were subsequently transferred to the stage of a Nikon A1 confocal microscope (Nikon, Japan) and connected to a syringe pump (SDR Scientific, USA) using a calibrated polyvinyl chloride tube (1.02 mm ID, Gilson, G.

将分离的嗜中性粒细胞接种在预先涂有Cell-Tak TM（Cat#CLS354240，Corning，USA）的μ-Slide 0.1（ibidi，Australia）内15分钟以确保细胞粘附。然后将嗜中性粒细胞在37℃下在HBSS缓冲液中加载2.5μMFluo-4 AM（Thermo Fisher Scientific，Australia）30分钟。随后将μ-载玻片通道转移到尼康A1共聚焦显微镜（Nikon，Japan）的阶段，并使用校准的聚氯乙烯管（1.02mm ID，Gilson，G）连接到注射泵（SDR Scientific，USA）。

Data availability

数据可用性

Data supporting the findings of this study are available within the paper, its supplementary information, and the source data file. A list of all antibodies and dyes used in this study is provided in the supplementary file. Additional data associated with the paper and source data file is shared via https://figshare.com/s/4a9fbd34041ee1a0740e. Source data are provided with this paper..

。补充文件中提供了本研究中使用的所有抗体和染料的列表。与纸张和源数据文件相关的其他数据通过https://figshare.com/s/4a9fbd34041ee1a0740e.本文提供了源数据。。

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Download referencesAcknowledgementsThe authors would like to acknowledge the Australian Research Council for the Linkage grant (LP190100728) to S.B. and K.K. and Discovery grant (DP200101248) to S.B., and the National Health and Medical Research Council for a L3 Investigator Fellowship support (GNT1174098) to K.P.

下载参考文献致谢作者要感谢澳大利亚研究委员会对S.B.和K.K.的链接资助（LP190100728）和对S.B.的发现资助（DP200101248），以及国家卫生与医学研究委员会对K.P.的L3研究员奖学金支持（GNT1174098）。

and an Idea grant (GNT2020197) to S.B, K.K. and K.P.Author informationAuthors and AffiliationsBaker Heart and Diabetes Institute, Melbourne, VIC, 3004, AustraliaSara Baratchi, Chanly Chheang, Ying Zhou, Angela Huang, Austin Lai & Karlheinz PeterDepartment of Cardiometabolic Health, University of Melbourne, Parkville, VIC, 3010, AustraliaSara Baratchi & Karlheinz PeterSchool of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, AustraliaSara Baratchi, Habiba Danish, Manijeh Khanmohammadi & Kylie M.

以及一笔Idea赠款（GNT2020197）给S.B，K.K.和K.P.作者信息作者和附属机构贝克心脏与糖尿病研究所，墨尔本，维多利亚州，3004，澳大利亚巴拉奇，Chanly Chheang，Ying Zhou，Angela Huang，Austin Lai＆Karlheinz PeterDepartment of Cardiometabolic Health，墨尔本大学，帕克维尔，维多利亚州，3010，澳大利亚巴拉奇＆Karlheinz PeterSchool of Health and Biomedical Sciences，RMIT University，Bundoora，维多利亚州，3083，澳大利亚巴拉奇，Habiba Danish，Manijeh Khanmohammadi＆Kylie M。

QuinnSchool of Engineering, RMIT University, Melbourne, VIC, 3000, AustraliaKhashayar KhoshmaneshAuthorsSara BaratchiView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsS.B. and K.P. conceived and supervised the study. S.B. designed the experiments, developed the methodology, analysed and interpreted data, coordinated and supervised the work, and wrote the manuscript with input from all authors. H.D., C.C., Y.Z., A.H., A.L.

PubMed谷歌学术贡献。B、 K.P.构思并监督了这项研究。S、 B.设计实验，开发方法，分析和解释数据，协调和监督工作，并在所有作者的投入下撰写手稿。H、哥伦比亚特区，Y.Z.，A.H.，A.L。

and M.K. performed experiments and analysed data. K.K. and K.M.Q. provided technical support and advice on data analysis and interpretation.Corresponding authorCorrespondence to.

M.K.进行了实验并分析了数据。K、 K.和K.M.Q.就数据分析和解释提供了技术支持和建议。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleBaratchi, S., Danish, H., Chheang, C. et al. Piezo1 expression in neutrophils regulates shear-induced NETosis.

转载和许可本文引用本文Baratchi，S.，Danish，H.，Chheang，C。等人。嗜中性粒细胞中Piezo1的表达调节剪切诱导的NETosis。

Nat Commun 15, 7023 (2024). https://doi.org/10.1038/s41467-024-51211-1Download citationReceived: 13 July 2023Accepted: 31 July 2024Published: 22 August 2024DOI: https://doi.org/10.1038/s41467-024-51211-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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