Neutrophils in polytrauma – from recruitment to phenotypic and functional reprogramming

摘要： 我的长期目标是确定在健康和疾病中调节中性粒细胞反应的机制， 它们是如何被慢性低度全身性炎症改变的。外伤是一种 导致年轻人死亡和残疾的主要原因是世界范围内的一个主要公共卫生问题。 已知中性粒细胞在损伤时具有快速和可塑性的炎症反应，其在损伤后大量表达。 创伤后招募的中性粒细胞在复杂的全身性炎症反应中起着至关重要的病理作用。 导致生命受到威胁的反应。慢性低度全身性“代谢性”炎症患者 表现出中性粒细胞反应和功能失调。因此，这些患者有很高的风险， 出现严重的并发症，并在创伤后表现出高死亡率。知识如何 在多发性创伤中，后炎症影响中性粒细胞反应是有限的，特别是在涉及 调节机制，协调和指导中性粒细胞募集到并发创伤性损伤的部位。 创伤影响中性粒细胞的表型和功能，从而损害中性粒细胞对抗感染的能力 而同时促进组织损伤表型，其导致整体免疫功能障碍。 中性粒细胞群的这些改变为继发性炎症并发症， 败血症、多器官衰竭（MOF）和医院感染，这些感染延迟恢复并可能导致残疾或 死亡目前还不清楚创伤性损伤部位如何重编程中性粒细胞，以及是否依赖于创伤 局部或患者的整体炎症状态。在这个MIRA应用程序中，我们计划调查 多发性创伤中中性粒细胞表型和功能调节的机制。我们将利用 以其光学透明性和易于遗传而闻名的非凡的斑马鱼动物模型， 药理学操作可视化，跟踪和deconvolute参与的分子机制， 中性粒细胞反应在多发性创伤在整个动物的背景下。我们将联合收割机结合我们的斑马鱼多发伤模型 和独特的全动物非侵入性活体成像方法，具有遗传操作和蛋白质，脂质， 转录本和中性粒细胞和并发创伤性损伤部位的表观遗传学分析，以评估1） 调节机制，协调中性粒细胞募集并发创伤性损伤，2）如何中性粒细胞 在创伤性损伤部位被重编程以产生逆转迁移的特异性中性粒细胞亚群， 创伤中的炎症传播，以及3）慢性炎症如何影响这些过程。我们的研究 将使我们更深入地了解参与多发性创伤炎症的中性粒细胞机制， 反应在健康和metainflammation设置。通过拟议研究获得的知识将 使我们能够操纵中性粒细胞反应作为一种手段，通过这种手段来改善创伤后患者的预后， 特别是在高危人群中。

Abstract: My long-term goal is to determine the mechanisms that regulate neutrophil response in health and disease and how they are altered by the presence of chronic low-grade systemic inflammation. Traumatic injuries are a leading cause of death and disability in younger people being a major public health problem worldwide. Neutrophils are known for their fast and moldable inflammatory response upon injury, which are massively recruited after trauma. Neutrophils play a crucial pathological role in the complex systemic inflammatory response that leads to life-threaten situations. Patients with chronic low-grade systemic "metabolic" inflammation display a dysregulated neutrophil response and function. Consequently, these patients are at high risk of developing serious complications and exhibit a high mortality rate after trauma. Knowledge of how metainflammation impacts neutrophil response in polytrauma is limited, particularly in what concerns the regulatory mechanisms that coordinate and direct neutrophil recruitment to sites of concurrent traumatic injuries. Trauma affects the phenotype and function of neutrophils, which impairs the neutrophil capacity to fight infections while at the same time promotes tissue damage phenotypes that contribute to the overall immune dysfunction. These alterations on neutrophil populations set the stage for secondary inflammatory complications such as sepsis, multiple organ failure (MOF), and nosocomial infections that delay recovery and can lead to disability or death. It is also unclear how traumatic injury sites reprogrammed neutrophils and if it is dependent of trauma localization, or the patient’s overall inflammatory status. In this MIRA application, we plan to investigate mechanisms involved in neutrophil phenotypic and functional modulation in polytrauma. We will take advantage of the remarkable zebrafish animal model known for its optical transparency and ease of genetic and pharmacological manipulation to visualize, track and deconvolute the molecular mechanism involved in the neutrophil response in polytrauma at a whole-animal context. We will combine our zebrafish polytrauma model and unique whole-animal non-invasive live imaging approach with genetic manipulation and protein, lipid, transcript, and epigenetic profiling of neutrophils and concurrent traumatic injury sites to evaluate 1) the regulatory mechanisms that coordinate neutrophil recruitment to concurrent traumatic injuries, 2) how neutrophils are reprogrammed at sites of traumatic injury to generate specific neutrophil subsets that reverse migrate and disseminate inflammation in trauma, and 3) how chronic inflammation impacts such processes. Our research will allow us to gain a deeper understanding of the neutrophil mechanisms involved in polytrauma inflammatory response in healthy and metainflammation settings. The knowledge achieved by the proposed research will enable us to manipulate neutrophil response as a means by which to improve patient outcomes following trauma, particularly in high-risk groups.