Neutrophil polarisation

中性粒细胞极化

• 批准号: BB/F021402/1
• 负责人: Guillaume Charras
• 金额: $ 81.66万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF021402%2F1
• 关键词: Neutrophil; polarisation

Neutrophils are the primary cells of the immune system responsible for detecting and preventing bacterial infections, as well as driving inflammation. Neutrophils circulate freely in the bloodstream, and when passing through an inflamed region attach the blood vessel wall, traverse the endothelium (transendothelial migration), and migrate through the connective tissue to the site of infection (chemotaxis). Prior to chemoattractant exposure, neutrophils are spherical and their actin cytoskeleton, the main regulator of cell shape, forms a peripheral shell. Upon stimulation, they become elongated with an F-actin rich lamellipodium that extends in the direction of the chemical gradient and start moving. The signalling cascade involved in the detection and transduction of chemoattractive signals is becoming progressively better understood; however, surprisingly little is known about actin dynamics or cortex mechanics during polarisation and migration. Studies of neutrophil locomotion to date have concentrated on movement on 2-D substrates. Physiologically, neutrophils spend most of their useful lifetime migrating in confined environments. Phenomenological descriptions of locomotion in 3-D suggest that it operates via different mechanisms than movement on flat surfaces. Despite its physiological importance, locomotion in 3-D has been largely ignored due to greater technical difficulties in examining it experimentally. We propose to examine neutrophil polarisation and locomotion in 3-D environments from a biophysical perspective focusing on the dynamics of the cytoskeleton and the mechanical forces at play. Understanding these phenomena will advance our knowledge of cell migration in confined environments, an area of particular relevance to antibacterial and inflammatory processes. To answer these questions, we will build a multidisciplinary team of scientists that will use a combination of microfluidic, microscopy, micromanipulation, and molecular cell biology techniques.

中性粒细胞是免疫系统的主要细胞，负责检测和预防细菌感染，以及驱动炎症。中性粒细胞在血液中自由循环，当穿过炎症区域时，它们附着在血管壁上，穿过内皮（跨内皮迁移），并通过结缔组织迁移到感染部位（趋化性）。在接触化学引诱剂之前，中性粒细胞是球形的，它们的肌动蛋白细胞骨架（细胞形状的主要调节剂）形成外周壳。一旦受到刺激，它们就会被富含f -肌动蛋白的片基拉长，并沿着化学梯度的方向延伸并开始移动。参与化学吸引信号的检测和转导的信号级联正逐渐得到更好的理解；然而，令人惊讶的是，在极化和迁移过程中，对肌动蛋白动力学或皮层力学知之甚少。迄今为止对中性粒细胞运动的研究主要集中在二维基质上的运动。生理上，中性粒细胞的大部分有用寿命都是在受限的环境中迁移的。对三维运动的现象学描述表明，它与平面上的运动通过不同的机制运作。尽管三维运动在生理上很重要，但由于实验上的技术困难，它在很大程度上被忽视了。我们建议从生物物理学的角度研究中性粒细胞极化和运动在三维环境中的作用，重点关注细胞骨架的动力学和发挥作用的机械力。了解这些现象将促进我们对密闭环境中细胞迁移的认识，这是一个与抗菌和炎症过程特别相关的领域。为了回答这些问题，我们将建立一个多学科的科学家团队，他们将使用微流体，显微镜，微操作和分子细胞生物学技术的组合。

项目成果

Mechanisms of leading edge protrusion in interstitial migration.

• DOI: 10.1038/ncomms3896
• 发表时间: 2013
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Wilson, Kerry;Lewalle, Alexandre;Fritzsche, Marco;Thorogate, Richard;Duke, Tom;Charras, Guillaume
• 通讯作者: Charras, Guillaume

Cellular control of cortical actin nucleation.

• DOI: 10.1016/j.cub.2014.05.069
• 发表时间: 2014-07-21
• 期刊: Current biology : CB
• 作者: Bovellan M;Romeo Y;Biro M;Boden A;Chugh P;Yonis A;Vaghela M;Fritzsche M;Moulding D;Thorogate R;Jégou A;Thrasher AJ;Romet-Lemonne G;Roux PP;Paluch EK;Charras G
• 通讯作者: Charras G

A phenomenological density-scaling approach to lamellipodial actin dynamics(†).

• DOI: 10.1098/rsfs.2014.0006
• 发表时间: 2014-12-06
• 期刊: Interface focus
• 影响因子: 4.4
• 作者: Lewalle A;Fritzsche M;Wilson K;Thorogate R;Duke T;Charras G
• 通讯作者: Charras G

A Worldwide Competition to Compare the Speed and Chemotactic Accuracy of Neutrophil-Like Cells.

• DOI: 10.1371/journal.pone.0154491
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Skoge M;Wong E;Hamza B;Bae A;Martel J;Kataria R;Keizer-Gunnink I;Kortholt A;Van Haastert PJ;Charras G;Janetopoulos C;Irimia D
• 通讯作者: Irimia D