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 它们是如何因慢性低度全身炎症而改变的。创伤是一种 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。 众所周知，中性粒细胞在受伤时会产生快速的、可塑的炎症反应，这种炎症反应 在创伤后被招募。中性粒细胞在复杂的全身炎症中起着重要的病理作用。 导致生命威胁情况的反应。慢性低度全身“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 创伤后出现严重并发症，死亡率高。了解如何 间质燃烧对多发伤患者中性粒细胞反应的影响是有限的，特别是在涉及 协调和引导中性粒细胞募集到并发创伤损伤部位的调节机制。 创伤影响中性粒细胞的表型和功能，从而削弱中性粒细胞抵抗感染的能力。 同时促进组织损伤表型，从而导致整体免疫功能障碍。 中性粒细胞数量的这些变化为继发性炎症并发症奠定了基础，如 脓毒症、多器官衰竭(MOF)和院内感染，延迟康复并可能导致残疾或 死亡。目前也不清楚创伤部位如何对中性粒细胞进行重新编程，以及它是否依赖于创伤。 定位，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 多发伤的中性粒细胞表型和功能调节机制。我们会利用这个优势 斑马鱼动物模型以其光学透明性和遗传和易感性而闻名 药物操作以可视化、跟踪和解开参与的分子机制 全动物环境下多发伤患者的中性粒细胞反应。我们将结合我们的斑马鱼多发性创伤模型 和独特的全动物非侵入性活体成像方法，结合基因操作和蛋白质、脂肪、 转录本，以及中性粒细胞和并发创伤损伤部位的表观遗传学特征，以评估1) 协调中性粒细胞募集到并发创伤损伤的调节机制，2)中性粒细胞如何 在创伤部位重新编程以产生特定的中性粒细胞亚群，这些亚群反向迁移和 在创伤中传播炎症，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中性粒细胞参与多发性创伤炎症反应的机制。 在健康和间歇燃烧环境下的反应。拟议的研究所获得的知识将 使我们能够操纵中性粒细胞的反应，作为一种改善创伤后患者预后的手段， 尤其是在高危人群中。

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.