Neutrophil extracellular traps orchestrate the immune response in Inflammatory Bowel Diseases

在过去的几十年里，中性粒细胞在炎症性肠病(IBD)发病机制中的作用一直是争论的焦点。中性粒细胞功能障碍是IBD发病的重要因素。粒细胞功能的特殊缺陷与人类瘘管性小肠结肠炎有关。然而，在粒细胞功能障碍的背景下导致肠道疾病的细胞和分子机制仍然不清楚。几年前，一种新的中性粒细胞效应机制被描述，中性粒细胞通过它排出染色质，形成中性粒细胞胞外陷阱(Nets)。这一过程依赖于活性氧(ROS)和组蛋白瓜氨酸氨基脱氨酶4(PAD14)的作用。最近已经描述了Nets和Net聚集体(AggNETs)的促炎和抗炎作用，但关于这一过程在肠道炎症中的功能作用的知识很少。在这个项目中，我们将描述Nets在小鼠肠道炎症和人类IBD过程中的功能作用。首先，我们将利用一组基因定义的模型来破译组蛋白瓜氨酸化、中性粒细胞中ROS产生的作用以及这两种效应机制的联合缺陷。我们认为，对各种肠道炎症模型的分析将对肠道疾病中的网织红细胞增多症有更深入的了解。其次，我们将分析IBD患者来源的中性粒细胞对一组确定的刺激做出反应的Net和aggNETs的能力，并在临床病程的背景下解释这些发现。我们的目标是进一步验证临床实践中常规的蚊虫感染检测方法。中性粒细胞功能障碍的免疫缺陷IBD患者的识别可能会对患者护理中的治疗决策产生重大影响。

The functional contribution of neutrophil granulocytes to the pathogenesis of inflammatory Bowel Diseases (IBD) such as Crohn's Disease and Ulcerative Colitis has been a matter of debate during the last decades. It has been proposed that neutrophil dysfunction is an important contributor to the pathogenesis of IBD. Specific defects of granulocyte function are associated with fistulizing enterocolitis in humans. However, the cellular and molecular mechanisms leading to intestinal disease in the context of granulocyte dysfunction remain elusive. Several years ago, a novel effector mechanism of neutrophil granulocytes has been described by which neutrophils extrude chromatin and form neutrophil extracellular traps (NETs). This process depends on reactive oxygen species (ROS) and histone citrullination by peptidyl arginine deiminase 4 (PAD14). Pro- and anti-inflammatory effects of NETs and NET aggregates (aggNETs) have been described recently, yet the knowledge about the functional role of this process in intestinal inflammation is scarce. In this project we will delineate the functional role of NETs in the course of intestinal inflammation in mice and IBD in humans. Firstly, we will make use of a set of genetically defined models in order to decipher the roles of histone citrullination, ROS generation in neutrophils and the combined defect of both effector mechanisms. We argue that the analysis of various models of intestinal inflammation will provide a sophisticated understanding of NETosis in enteric diseases. Secondly, we will analyze the capacity of IBD patient-derived neutrophils to produce NETs and aggNETs in response to a defined set of stimuli and interpret the findings in the context of the clinical course of disease. We aim to further validate a routine NETosis assay for clinical practice. The identification of immunodeficient IBD patients with neutrophil dysfunction may strongly impact therapeutic decisions in patient care.