Targeted modulation of neutrophil activity: impact on intestinal immunopathology

肠道免疫系统面临的挑战是对共生微生物群和食物抗原保持无反应，同时能够在面对病原体时迅速做出免疫反应。有四种主要成分有助于肠道内环境的稳定，包括上皮细胞、免疫细胞、肠道微生物和饮食代谢物。严格控制免疫反应的重要性在慢性自身炎症性肠病(IBD)的背景下被强调，如克罗恩病(CD)和溃疡性结肠炎(UC)，其中针对共生的免疫反应变得紊乱。虽然对IBD的大部分研究都集中在由特定的先天性免疫细胞(称为单核细胞)和获得性免疫细胞(称为T辅助细胞(Th)细胞)驱动的免疫病理学高峰上，但对肠道炎症启动的第一个决定性事件关注较少。特别是，另一种类型的先天性免疫细胞，称为中性粒细胞，在结肠炎期间的具体作用还没有明确描述。中性粒细胞迅速穿过血管内皮细胞到达肠道固有层。在人类结肠活检组织中，它们的存在被认为是活动性疾病的迹象，并越来越多地被用作UC临床试验的次要终点。在IBD患者的外周血和粘膜组织中，它们的表型和效应功能都发生了变化。中性粒细胞的激活也被报道影响T细胞群，特别是影响致病的Th细胞。然而，中性粒细胞在病理性肠炎的启动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。我们最近的发现表明，尽管中性粒细胞在组织中的停留时间有限，但它们可以定制自己的属性来安装特定的和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器功能的关键分子调节因子。本项目将使用最近产生的独特工具，如基因修饰的体外和体内模型，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，研究控制调节中性粒细胞活性对肠炎症免疫病理的功能影响。这可能导致一类新的治疗策略的开发，基于对中性粒细胞生物学的选择性调节，以对抗病理性炎症和相关的炎症性疾病，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.