Kindlin-3 signaling in neutrophils

中性粒细胞中的 Kindlin-3 信号传导

• 批准号: 10576419
• 负责人: Yan-Qing Ma
• 金额: $ 45.78万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576419
• 关键词: Acute Lung Injury; Anti-Inflammatory Agents; Arginine; Binding; Biology; COVID-19; Cells; Chemotaxis; Chronic; Co-Immunoprecipitations; Cytoplasmic Tail; Decision Trees; Disease; Endotoxemia; Event; Excision; Goals; HL-60 Cells; Hematopoietic; Human; Hydrolase; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Integrin Binding; Integrin beta Chains; Integrins; Lysine; Mediating; Methods; Mus; Neutrophil Activation; Neutrophil Infiltration; Pathologic; Play; Predisposition; Process; Production; Property; Reactive Oxygen Species; Regulation; Research Project Grants; Resistance; Role; Signal Transduction; Site; Sterility; Stimulus; Testing; Tissues; Ubiquitin; Ubiquitination; Yeasts; experimental study; extracellular; inflammatory modulation; insight; multicatalytic endopeptidase complex; mutant; neutrophil; novel; response; screening; ubiquitin-protein ligase; yeast two hybrid system

PROJECT SUMMARY/ABSTRACT Inflammation plays a pivotal role in the rapid removal of harmful stimuli, either sterile or infectious; however, uncontrolled inflammation can lead to a variety of chronic inflammatory disorders. Neutrophils constitute the front line of the innate immune response, and swiftly undergo a carefully choreographed process to locate and destroy potentially pathological threats. Neutrophil recruitment is an integrin-dependent, chemotaxis-directed process that is followed by production of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs), together which serve to remove or kill the offending agents. To minimize collateral damage to host tissues, however, the killing functions of neutrophils must be carefully regulated in both a temporally and spatially controlled manner; the mechanisms at play to regulate neutrophil activation, however, remain poorly understood. Kindlin-3, an integrin β cytoplasmic domain binding partner, and an essential integrin activator in cells of hematopoietic origin, is known to play an important role in promoting integrin-mediated neutrophil recruitment to the sites of inflammation. Paradoxically, however, we have recently discovered that neutrophil kindlin-3 also acts to suppress ROS production and NET release in an integrin-binding independent manner. Thus, kindlin-3 in neutrophils possesses both pro- and anti-inflammatory properties, indicating that it may function as a bifunctional modulator of neutrophil activation. Interestingly, our preliminary studies have revealed that neutrophil kindlin-3 unexpectedly becomes degraded upon inflammatory challenges. Based on these findings, we propose that degradation of neutrophil kindlin-3 is a key step in the cellular decision tree regulating neutrophil activation under inflammatory conditions. The purpose of this application, therefore, is to explore novel, heretofore unexplored mechanisms regulating kindlin-3 degradation and to examine its functional significance in inflammatory responses. Two Specific Aims are proposed. In Specific Aim 1, we will determine the mechanism by which kindlin-3 undergoes degradation in stimulated neutrophils, including both human and mouse neutrophils. In Specific Aim 2, we will determine the functional significance of kindlin-3 degradation in neutrophils in response to inflammatory challenges, such as under pathological conditions of endotoxemia and acute lung injury. These timely and complementary studies will establish an important and novel role for kindlin-3 in neutrophils in modulating inflammatory responses. Findings made will fill important gaps in our understanding of neutrophil biology, and may lead to novel opportunities for developing more specific and safer anti-inflammatory strategies for treating complications in a whole host of inflammatory diseases, including the recently described inflammatory complications present in COVID-19.

项目摘要/摘要 炎症在迅速清除有害刺激方面起着关键作用，无论是无菌的还是有感染性的；然而， 不加控制的炎症会导致各种慢性炎症性疾病。中性粒细胞构成了 先天免疫反应的前线，并迅速经历一个精心设计的过程来定位和 摧毁潜在的病理性威胁。中性粒细胞募集是一种整合素依赖、趋化导向的过程 产生活性氧(ROS)和释放中性粒细胞胞外的过程 陷阱(网)，一起用来清除或杀死违规的代理人。将附带损害降至最低 然而，宿主组织中性粒细胞的杀伤功能必须在临时和 空间控制的方式；然而，调节中性粒细胞激活的机制仍然很差 明白了。Kindlin-3，整合素β胞浆结构域结合伙伴，以及在 已知造血源细胞在促进整合素介导的中性粒细胞中发挥重要作用 向炎症部位募集。然而，矛盾的是，我们最近发现中性粒细胞 Kindlin-3还以整合素结合非依赖的方式抑制ROS的产生和净释放。 因此，中性粒细胞中的kindlin-3同时具有促炎和抗炎特性，这表明它可能 作为中性粒细胞激活的双功能调节剂。有趣的是，我们的初步研究 显示中性粒细胞Kindlin-3在炎症挑战时意外降解。基于 这些发现，我们提出，中性粒细胞Kindlin-3的降解是细胞决策树中的关键步骤 调节炎症条件下中性粒细胞的激活。因此，此应用程序的目的是 探索调节kindlin-3降解的新的、迄今未知的机制，并检测其 炎症反应中的功能意义。提出了两个具体目标。在具体目标1中，我们将 确定Kindlin-3在刺激的中性粒细胞中降解的机制，包括两者 人类和小鼠的中性粒细胞。在具体目标2中，我们将确定kindlin-3的功能意义 中性粒细胞对炎症挑战的反应，例如在病理条件下 内毒素血症和急性肺损伤。这些及时和互补的研究将建立一个重要的和 中性粒细胞中kindlin-3在调节炎症反应中的新作用。所做的发现将填补重要的 在我们对中性粒细胞生物学的理解上的差距，并可能导致开发更多的新机会 治疗全身炎性疾病并发症的特异和更安全的抗炎策略 疾病，包括最近描述的新冠肺炎中存在的炎症并发症。