Role of the cytoskeleton in neutrophil activation and inflammation

细胞骨架在中性粒细胞激活和炎症中的作用

• 批准号: RGPIN-2018-05572
• 负责人: Girard, Denis
• 金额: $ 2.62万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=651946
• 关键词: Role; cytoskeleton; neutrophil; activation; inflammation

* *** ** ** *****The*cytoskeleton is a dynamic structure composed of numerous proteins involved in*different cellular functions. This is particularly true for human*polymorphonuclear neutrophils (PMNs), the most abundant leukocytes in the blood*and key player cells in inflammation. Despite this, the role of cytoskeletal*proteins (CKp) in inflammation remains unclear. Inflammation is a normal immune*response against a variety of assaults including not only pathogens, but also*injuries, drugs, chemicals, and, more recently, nanoparticles (NPs), that is transient and resolved under normal*circumstances. However, when deregulation occurs, inflammation can persist,*leading to undesired effects, including cell death, tissue damage and diseases.*Because the resolution of inflammation largely occurs by the elimination of*apoptotic PMNs by professional phagocytes (efferocytosis),*it is important to understand the mode of action of PMN activators and to*elucidate how they alter the cytoskeleton. Recently, we have shown that some*CKp are expressed on the cell surface of apoptotic PMNs, including vimentin,*lamin B, ezrin, moesin and more recently, α-fodrin, but their role remains*elusive. As our research program evolves over time, we have recently*demonstrated that some NPs are new agents that can also induce human PMN*apoptosis, cytoskeletal rearrangement as well as inflammation. For example,*gold NPs were found to induce apoptosis, endoplasmic reticulum stress events*and cleavage of some CKp in human PMNs, but did not increase their cell surface*expression during apoptosis. This indicates that cell surface expression of CKp*could even be a context-dependent phenomenon according to the proapoptotic agent*tested. However, this remains to be determined. * ***In the*present short-term objectives, we will determine:***i) if*other CKp are degraded during PMN apoptosis and expressed at the cell surface*of apoptotic PMNs.***ii) if*the cell surface CKp are involved in efferocytosis.***iii) if a*given CKp is involved in PMN functions *** *The long-term objectives are: i) to catalogue which CKp are expressed at the cell surface of*apoptotic PMNs; ii) to*determine the importance of the cytoskeleton during efferocytosis and other PMN*functions; and iii) to guide*future studies on specific CKp and their roles during PMN activation and*inflammation. ***Understanding*the molecular and cell biology events occurring during cytoskeleton*reorganisation in human PMNs are fundamental for better understanding not only*the biology of these cells, but will also increase our knowledge on general*inflammation. In the very long term, it is highly predictable that our results*will allow the generation of knockout mice for a given CKp. This will represent*powerful tools for the scientific community and will help to better increase*our knowledge on the importance of the cytoskeleton and CKp in leukocyte*cellular physiology and inflammation. ******

* *** ** ** ** 细胞骨架是一种动态结构，由参与不同细胞功能的许多蛋白质组成。这对于人类 * 多形核中性粒细胞（PMNs）尤其如此，PMNs是血液中最丰富的白细胞 *，也是炎症中的关键细胞。尽管如此，细胞骨架 * 蛋白（CKp）在炎症中的作用仍不清楚。炎症是一种针对各种攻击的正常免疫反应，这些攻击不仅包括病原体，还包括损伤、药物、化学品，以及最近的纳米颗粒（NP），在正常情况下是短暂的和可解决的。然而，当失调发生时，炎症可能会持续存在，* 导致不良影响，包括细胞死亡，组织损伤和疾病。由于炎症的消退主要是通过吞噬细胞清除凋亡的中性粒细胞（吞噬作用）来实现的，因此了解中性粒细胞激活剂的作用方式并阐明它们如何改变细胞骨架是很重要的。最近，我们发现一些CKp在凋亡的中性粒细胞的细胞表面表达，包括波形蛋白、核纤层蛋白B、埃兹蛋白、膜突蛋白和最近的α-胞衬蛋白，但它们的作用仍不清楚。随着我们的研究项目的不断发展，我们最近证明了一些NP是新的药物，也可以诱导人PMN凋亡，细胞骨架重排以及炎症。例如，* 金纳米颗粒被发现诱导细胞凋亡，内质网应激事件 * 和切割的一些人中性粒细胞的CKp，但没有增加他们的细胞表面 * 在细胞凋亡过程中的表达。这表明，根据所测试的促凋亡剂 *，CKp* 的细胞表面表达甚至可能是环境依赖性现象。然而，这一点仍有待确定。* * 在 * 目前的短期目标中，我们将确定：*i）* 其他CKp是否在PMN凋亡期间降解并在凋亡PMN的细胞表面 * 表达。* ii）如果 * 细胞表面CKp参与胞浆细胞增多症。*长期目标是：i）分类哪些CKp在凋亡的PMN的细胞表面表达; ii）确定细胞骨架在胞浆细胞增多和其他PMN功能中的重要性; iii）指导将来对特定CKp及其在PMN活化和炎症中的作用的研究。了解人类中性粒细胞细胞骨架重组过程中发生的分子和细胞生物学事件不仅是更好地了解这些细胞生物学的基础，而且还将增加我们对一般炎症的了解。从长远来看，我们的结果 * 将允许产生给定CKp的敲除小鼠是高度可预测的。这将代表科学界的强大工具，并将有助于更好地增加我们对细胞骨架和CKp在白细胞细胞生理学和炎症中的重要性的认识。******