Targeted modulation of neutrophil activity: impact on intestinal immunopathology

中性粒细胞活性的靶向调节：对肠道免疫病理学的影响

• 批准号: MR/X000605/1
• 负责人: Irina Udalova
• 金额: $ 84.87万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX000605%2F1
• 关键词: Targeted; modulation; neutrophil; activity; impact

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.

肠道免疫系统面临的挑战是对肠道微生物菌群和食物抗原保持无反应，同时能够在面对病原体时产生快速免疫反应。四个主要组成部分有助于肠道内稳态，包括上皮细胞，免疫细胞，肠道微生物和饮食代谢物。在慢性自身炎性肠病（IBD），如克罗恩病（CD）和溃疡性结肠炎（UC）的背景下，强调了严格控制免疫应答的重要性，其中针对结肠的免疫应答变得失调。虽然对IBD的大部分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T辅助细胞（Th）细胞）驱动的免疫病理学峰值上，但肠道炎症起始中的第一个定义事件受到的关注较少。特别是，另一种类型的先天免疫细胞，称为中性粒细胞，在结肠炎期间的具体作用尚未明确界定。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，它们显示改变的表型和效应子功能。据报道，中性粒细胞活化也影响T细胞群，特别是影响致病性Th细胞。然而，中性粒细胞对病理性肠道炎症的起始和传播的贡献程度，它们与其他免疫细胞的相互作用以及留在组织上的免疫印记，在很大程度上仍未被探索。我们最近的研究结果表明，尽管在组织中的停留时间有限，但中性粒细胞可以调整其特性，以产生特异性和内在调节的炎症反应。此外，我们已经确定了关键的分子调节剂，特别是控制中性粒细胞成熟或效应功能。该项目将使用最近产生的独特工具，如遗传修饰的体外和体内模型，新发现的化学抑制剂等，以及尖端的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学的功能影响。这可能会导致一类新的治疗策略的发展，基于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。