Targeted modulation of neutrophil activity: impact on intestinal immunopathology

肠道免疫系统面临着对共生菌群和食物抗原保持无反应的挑战，同时能够在面对病原体时进行快速免疫反应。肠道稳态有四个主要组成部分，包括上皮细胞、免疫细胞、肠道微生物和膳食代谢物。在慢性自身炎症性肠病（IBD），如克罗恩病（CD）和溃疡性结肠炎（UC）的背景下，对共生菌的免疫反应变得失调，强调了严格控制免疫反应的重要性。虽然对IBD的许多研究都集中在由特异性先天免疫细胞（称为单核细胞）和适应性免疫细胞（称为辅助性T细胞）驱动的免疫病理高峰上，但肠道炎症起始的第一个决定性事件却很少受到关注。特别是，另一种称为中性粒细胞的先天免疫细胞在结肠炎中的具体作用尚未明确描述。中性粒细胞迅速穿过血管内皮到达肠固有层。它们在人类结肠活检中的存在被认为是活动性疾病的标志，并且越来越多地被用作UC临床试验的次要终点。在IBD患者的外周血和粘膜组织中，它们表现出改变的表型和效应功能。中性粒细胞活化也被报道影响T细胞群，特别是影响致病性Th细胞。然而，中性粒细胞在病理性肠道炎症的发生和传播中的作用程度，它们与其他免疫细胞的相互作用以及在组织上留下的免疫印记，在很大程度上仍未被探索。我们最近的研究结果表明，尽管中性粒细胞在组织中的停留时间有限，但它们可以调整自己的特性，以产生特定的、内在调节的炎症反应。此外，我们已经确定了专门控制中性粒细胞成熟或效应功能的关键分子调节因子。本项目将利用最近产生的独特工具，如转基因体外和体内模型，新发现的化学抑制剂等，以及尖端成像和单细胞基因组方法，研究中性粒细胞活性的控制调节对肠道炎症免疫病理的功能影响。这可能会导致一种基于中性粒细胞生物学选择性调节的新型治疗策略的发展，以对抗病理性炎症和相关炎症疾病，如IBD。

The intestinal immune system encounters the challenge of remaining unresponsive to the commensal microflora and food antigens whilst being able to mount a rapid immune response upon facing pathogens. Four major components contribute to gut homeostasis, including the epithelium, immune cells, intestinal microbes, and dietary metabolites. The importance of a tight control of immune response is emphasized in the context of chronic auto-inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and Ulcerative Colitis (UC), where an immune response against commensals becomes dis-regulated. While much of investigation into IBD has been focused on the peak of immunopathology driven by specific innate immune cells, called monocytes, and adaptive immune cells, called T helper (Th) cells, the first defining events in initiation of intestinal inflammation received less attention. Particularly, the specific role of another type of innate immune cells, called neutrophils, during colitis has not been clearly delineated. Neutrophils rapidly traverse the vascular endothelium to reach the intestinal lamina propria. Their presence in human colonic biopsies is considered to be a sign of active disease and is increasingly used as a secondary endpoint in clinical trials in UC. In both peripheral blood and mucosal tissue of IBD patients, they display altered phenotype and effector functions. Neutrophil activation was also reported to affect T cell populations, specifically influencing pathogenic Th cells. However, the extent of neutrophil contributions into the initiation and propagation of pathological intestinal inflammation, their interactions with other immune cells and immune-imprinting left on the tissue, remain largely unexplored. Our recent findings demonstrate that, despite limited residence times in tissues, neutrophils can tailor their properties to mount specific and intrinsically regulated inflammatory response. Moreover, we have identified key molecular regulators specifically controlling neutrophil maturation or effector functions. This project will examine the functional impact of controlled modulation of neutrophil activity on the immunopathology of intestinal inflammation using the recently generated unique tools, such as genetically modified in vitro and in vivo models, newly discovered chemical inhibitors etc, and cutting-edge imaging and single cell genomic approaches. This may lead to the development of a new class of therapeutic strategies, based on selective modulation of neutrophil biology, to combat pathological inflammation and associated inflammatory disorders, such as IBD.