Neutrophil extracellular traps orchestrate the immune response in Inflammatory Bowel Diseases

中性粒细胞在炎症性肠病（IBD）如克罗恩病和溃疡性结肠炎的发病机制中的作用在过去几十年中一直是一个有争议的问题。中性粒细胞功能障碍是IBD发病机制的重要因素。粒细胞功能的特异性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难以捉摸。几年前，已经描述了中性粒细胞的一种新的效应器机制，通过该机制中性粒细胞挤出染色质并形成中性粒细胞胞外陷阱（NETs）。这一过程依赖于活性氧（ROS）和组蛋白瓜氨酸肽酰精氨酸脱亚胺酶4（PAD 14）。最近已经描述了NET和NET聚集体（aggNET）的促炎和抗炎作用，但是关于该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NET在小鼠肠道炎症和人类IBD过程中的功能作用。首先，我们将利用一套遗传定义的模型，以破译组蛋白瓜氨酸的作用，ROS的产生在中性粒细胞和两种效应机制的组合缺陷。我们认为，分析各种模型的肠道炎症将提供一个复杂的理解NETosis在肠道疾病。其次，我们将分析IBD患者来源的中性粒细胞产生NET和aggNET的能力，以响应一组定义的刺激，并在疾病的临床病程的背景下解释的结果。我们的目标是进一步验证用于临床实践的常规NETosis测定。中性粒细胞功能障碍的免疫缺陷IBD患者的鉴定可能会强烈影响患者护理中的治疗决策。

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.