Kindlin-3 signaling in neutrophils

项目总结/摘要 炎症在快速去除有害刺激（无论是无菌的还是传染性的）方面发挥着关键作用;然而， 不受控制的炎症可导致多种慢性炎性疾病。中性粒细胞构成了 先天免疫反应的前线，并迅速经历精心设计的过程，以定位和 摧毁潜在的病理威胁神经元募集是一种整合素依赖性、趋化性导向的 随后产生活性氧（ROS）并释放中性粒细胞胞外 陷阱（NET），一起用于清除或杀死违规代理。为了尽量减少对 然而，在宿主组织中，嗜中性粒细胞的杀伤功能必须在时间和时间上仔细调节。 空间控制的方式;机制在发挥调节中性粒细胞活化，但是，仍然很差， 明白Kindlin-3，一种整合素β胞质结构域结合伴侣，和一种重要的整合素激活剂， 造血来源的细胞，已知在促进整合素介导的中性粒细胞 募集到炎症部位。然而，奇怪的是，我们最近发现， Kindlin-3还以不依赖于整联蛋白结合的方式抑制ROS产生和NET释放。 因此，中性粒细胞中的kindlin-3具有促炎和抗炎特性，表明它可能 作为中性粒细胞活化的双功能调节剂发挥作用。有趣的是，我们的初步研究 揭示了中性粒细胞Kindlin-3在炎症激发时意外地被降解。基于 根据这些发现，我们认为中性粒细胞kindlin-3的降解是细胞决策树的关键步骤。 在炎症条件下调节嗜中性粒细胞活化。因此，本申请的目的是 探索新的，迄今尚未探索的机制，调节kindlin-3降解，并检查其 在炎症反应中的功能意义。提出了两个具体目标。具体目标1： 确定kindlin-3在刺激的中性粒细胞中降解的机制，包括 人和小鼠嗜中性粒细胞。在具体目标2中，我们将确定kindlin-3的功能意义 在中性粒细胞中的降解响应于炎性挑战，例如在炎症的病理条件下， 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调查结果将填补重要 我们对中性粒细胞生物学的理解存在差距，并可能导致开发更多的新机会。 特异性和更安全的抗炎策略，用于治疗各种炎症性 疾病，包括最近描述的COVID-19中存在的炎症并发症。

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.