Investigating the lymphatic system in intestinal inflammation

研究肠道炎症中的淋巴系统

• 批准号: MR/V001949/1
• 负责人: Rahul Ravindran
• 金额: $ 38.16万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV001949%2F1
• 关键词: Investigating; lymphatic; system; intestinal; inflammation

Context and clinical relevanceInflammatory bowel disease (IBD), comprising of Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic immune-mediated inflammatory disease that predominantly affects the gastrointestinal tract. Over two million people in Europe are affected with a prevalence exceeding 0.3% and its incidence is rising in the developing world. Various genetic and environmental factors have been implicated in the development of IBD but it remains incompletely understood. Several drug classes exist to treat IBD; however, none of these therapies lead to a state of permanent drug free remission and so optimal management remains a major clinical challenge. The variable response to treatment suggests different underlying disease processes over time and highlights the need for a deeper understanding of the cellular basis of IBD in order to develop innovative therapeutics.Lymphatics as a mechanism to allow exit of inflammatory cellsLymphatic vessels are a parallel vascular system to the blood vessels and are widely distributed across the body. They have a key role in permitting excess fluid to drain back to the heart and so serve to maintain fluid balance in the body. Furthermore, they play an essential role in facilitating an appropriate immune response. Their role in inflammation has been relatively neglected despite several reports of biopsies from patients with both Crohn's Disease and Ulcerative Colitis identifying increased lymphatic vessel density in the intestine. More recently evidence has emerged that in IBD the outflow of immune cells and fluid through the lymphatic vessels appears to be impaired in areas draining from the gut confirming that IBD is associated with observable structural changes in the lymphatic vessels. Despite these descriptive reports, it is unclear to what degree altered lymphatic function impacts on the resolution of inflammation in IBD.Experiments with animal models have provided valuable insights into the role of the lymphatics in inflammation. We know that the stimulation of lymphatic vessel growth (lymphangiogenesis) in mouse models improves inflammation in the colon, as well as the skin, joint and heart. Furthermore, inhibition of lymphatics worsens colonic inflammation, skin inflammation, arthritis and resolution from heart attack in mouse models. This highlights the importance of adequate lymphatic drainage of immune cells to allow resolution of inflammation. These reports strongly suggest that the lymphatic system is a possible way to improve inflammation and thus warrants further study in IBD.Experimental aims and objectives, and potential applications and benefitsLittle is known regarding the alterations in colonic lymphatics in response to inflammation and resolution. New technologies are emerging which allow individual cells to be investigated and characterised in the colon. We will use these to study variation in lymphatic endothelial cells as well as the interactions between lymphatic cells and their regulators in the colon. This will enable us to develop a much-needed understanding of what these vessels are doing. Once this part of the project is achieved we will proceed to test how manipulating the lymphatic system affects the resolution of colonic inflammation using animal models of colitis. Understanding the mechanisms of the resolution of intestinal inflammation will help serve the ultimate aim of translating this therapeutically to switch off chronic inflammation in the gut and help to treat patients with IBD.

背景和临床相关性炎症性肠病(IBD)包括克罗恩病(CD)和溃疡性结肠炎(UC)，是一种主要影响胃肠道的慢性免疫介导性炎症性疾病。欧洲有200多万人受到影响，患病率超过0.3%，在发展中国家，其发病率正在上升。多种遗传和环境因素参与了IBD的发生发展，但仍不完全清楚。有几种药物类别可以治疗IBD；然而，这些治疗方法都不会导致永久的药物无症状缓解状态，因此最佳治疗仍然是一个主要的临床挑战。对治疗的不同反应表明随着时间的推移，不同的潜在疾病过程，并强调需要更深入地了解IBD的细胞基础，以开发创新的治疗方法。淋巴学作为一种允许炎细胞退出的机制淋巴管是与血管平行的血管系统，广泛分布于全身。它们在允许多余的液体回流到心脏，从而维持体内的液体平衡方面起着关键作用。此外，它们在促进适当的免疫反应方面起着至关重要的作用。它们在炎症中的作用被相对忽视，尽管有几份来自克罗恩病和溃疡性结肠炎患者的活检报告表明，肠道中的淋巴管密度增加。最近出现的证据表明，在IBD中，免疫细胞和液体通过淋巴管的流出似乎在从肠道引流的区域受到损害，证实IBD与淋巴管中可见的结构变化有关。尽管有这些描述性报告，但尚不清楚淋巴功能改变在多大程度上影响IBD炎症的消退。动物模型实验为淋巴管在炎症中的作用提供了有价值的见解。我们知道，在小鼠模型中刺激淋巴管生长(淋巴管生成)可以改善结肠以及皮肤、关节和心脏的炎症。此外，抑制淋巴管会恶化小鼠模型的结肠炎、皮肤炎、关节炎和心脏病发作的缓解。这突出了充分的免疫细胞淋巴引流的重要性，以允许炎症的消退。这些报告强烈表明淋巴系统是改善炎症的一种可能途径，因此值得在IBD中进一步研究。实验的目的和目标，以及潜在的应用和好处关于结肠淋巴管在炎症和消退过程中的变化知之甚少。新的技术正在出现，这些技术允许在结肠中对单个细胞进行研究和表征。我们将利用这些来研究淋巴管内皮细胞的变异，以及淋巴管细胞和它们在结肠中的调节因子之间的相互作用。这将使我们能够对这些船只正在做的事情有一个非常必要的了解。一旦项目的这一部分完成，我们将继续使用结肠炎的动物模型来测试操纵淋巴系统如何影响结肠炎的消退。了解肠道炎症消退的机制将有助于将其转化为治疗的最终目标，以关闭肠道的慢性炎症，并帮助治疗IBD患者。

项目成果

Author Correction: Inflammation across tissues: can shared cell biology help design smarter trials?

作者更正：跨组织炎症：共享细胞生物学可以帮助设计更智能的试验吗？

• DOI: 10.1038/s41584-023-01049-6
• 发表时间: 2023
• 期刊: Nature reviews. Rheumatology
• 作者: Hosack T

ILC3-induced regulatory T cells are directed by gut microorganisms.

ILC3 诱导的调节性 T 细胞受肠道微生物的指导。

• DOI: 10.1038/s41577-022-00697-1
• 发表时间: 2022
• 期刊: Nature reviews. Immunology
• 作者: Ravindran R

Inflammation across tissues: can shared cell biology help design smarter trials?

• DOI: 10.1038/s41584-023-01007-2
• 发表时间: 2023-09-04
• 期刊: NATURE REVIEWS RHEUMATOLOGY
• 影响因子: 33.7
• 作者: Hosack, Tom;Thomas, Tom;Buckley, Christopher Dominic
• 通讯作者: Buckley, Christopher Dominic

Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases.

• DOI: 10.1016/j.medj.2022.05.002
• 发表时间: 2022-07-08
• 期刊: MED
• 影响因子: 17
• 作者: Korsunsky, Ilya;Wei, Kevin;Pohin, Mathilde;Kim, Edy Y.;Barone, Francesca;Major, Triin;Taylor, Emily;Ravindran, Rahul;Kemble, Samuel;Watts, Gerald F. M.;Jonsson, A. Helena;Jeong, Yunju;Athar, Humra;Windell, Dylan;Kang, Joyce B.;Friedrich, Matthias;Turner, Jason;Nayar, Saba;Fisher, Benjamin A.;Raza, Karim;Marshall, Jennifer L.;Croft, Adam P.;Tamura, Tomoyoshi;Sholl, Lynette M.;Vivero, Marina;Rosas, Ivan O.;Bowman, Simon J.;Coles, Mark;Frei, Andreas P.;Lassen, Kara;Filer, Andrew;Powrie, Fiona;Buckley, Christopher D.;Brenner, Michael B.;Raychaudhuri, Soumya
• 通讯作者: Raychaudhuri, Soumya

IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies.

• DOI: 10.1038/s41591-021-01520-5
• 发表时间: 2021-11
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Friedrich M;Pohin M;Jackson MA;Korsunsky I;Bullers SJ;Rue-Albrecht K;Christoforidou Z;Sathananthan D;Thomas T;Ravindran R;Tandon R;Peres RS;Sharpe H;Wei K;Watts GFM;Mann EH;Geremia A;Attar M;Oxford IBD Cohort Investigators;Roche Fibroblast Network Consortium;McCuaig S;Thomas L;Collantes E;Uhlig HH;Sansom SN;Easton A;Raychaudhuri S;Travis SP;Powrie FM
• 通讯作者: Powrie FM