Investigating the function of group 3 innate lymphoid cells in the renal tract

研究肾道中第 3 组先天淋巴细胞的功能

• 批准号: MR/N024907/1
• 负责人: Menna Clatworthy
• 金额: $ 79.27万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN024907%2F1
• 关键词: Investigating; function; group; innate; lymphoid

The kidneys play a critical role in cleaning the blood and controlling the body's water balance. Unfortunately, their function can be affected by a number of common diseases that can be life-threatening, including infection. Urinary tract infections (UTIs) are common, affecting up to half of women at some point in their lifetime. Recurrent infections can cause scarring that leads to permanent kidney damage and even kidney failure. All of the body's tissues house cells of the immune system. These sentinels stand guard in tissues and alert the body to infection by starting an inflammatory response. In the kidney, the response of immune sentinels to infection or tissue damage determines the extent of inflammation, and this can influence whether bacteria are cleared, whether there is collateral damage, and ultimately whether the function of the kidneys recovers or develops scarring. At present, we don't fully understand what type of tissue-resident immune cells live in human kidneys and bladder or their exact function. Addressing this challenge will help us to development better treatments for diseases that affect the kidney, including UTIs.In the last 5 years, a new family of immune cells have been discovered, the innate lymphoid cells (ILCs). These cells act as tissue sentinels, producing chemical signals (cytokines) that activate the immune system. One member of the ILC family, the ILC3s, have been found to be enriched in the intestine where they prevent the invasion of bacteria from the gut and produce factors that maintain the health of tissue cells. There is currently no information on whether there are ILC3s in human kidneys and bladder. We were interested in finding out if ILC3s could be important in these tissues and performed some preliminary experiments. Excitingly, we found ILC3s in mouse and human kidneys and bladder.The objective of this project is to find out what exactly they are doing, as follows:1. Where ILC3s are positioned in kidneys and bladder and whether they are situated near other immune sentinels.2. What sort of immune signalling molecules (chemokines and cytokines) are produced by ILC3s at during health and in response to the bacteria that cause UTIs. We can use mouse models and human tissues that have been donated for transplant, but cannot be used.3. How ILC3s patrol the kidney and bladder and whether they form interactions with other immune cells. To answer this question we will use a special sort of microscope and mice that have fluorescently labelled ILC3s. We have developed a protocol that allows us to image the cells in real time in the kidney and bladder, so we can begin to investigate the factors that control their movement and their interactions with other immune cells.4. Whether outcome and disease severity in UTI is affected by an absence of ILC3s, using mice that lack ILC3s due to genetic deletion of a factor that is required for their development.Elucidating the workings of ILC3s will help us to understand whether they contribute to helpful immune responses that clear bacteria in the renal tract. This will being to enable us to harness their useful functions to develop better therapeutic strategies that might reduce the frequency of UTIs or the scarring that can be associated with recurrent infections. In the long run, this could prevent patients from getting kidney failure and could help prolong the life of kidney transplants, which can also be damaged by recurrent infection.

肾脏在清洁血液和控制体内水分平衡方面起着至关重要的作用。不幸的是，它们的功能会受到包括感染在内的一些可能危及生命的常见疾病的影响。尿路感染（uti）很常见，多达一半的女性在一生中的某个时候会受到影响。反复感染会造成疤痕，导致永久性肾脏损伤甚至肾衰竭。身体的所有组织都容纳免疫系统的细胞。这些哨兵在组织中站岗，并通过启动炎症反应来提醒身体感染。在肾脏中，免疫哨兵对感染或组织损伤的反应决定了炎症的程度，这可以影响细菌是否被清除，是否有附带损伤，最终影响肾脏功能是恢复还是形成疤痕。目前，我们还不完全了解人体肾脏和膀胱中是什么类型的组织驻留免疫细胞或它们的确切功能。解决这一挑战将有助于我们开发出更好的治疗肾脏疾病的方法，包括尿路感染。在过去的五年中，人们发现了一种新的免疫细胞家族，即先天淋巴样细胞（ILCs）。这些细胞充当组织哨兵，产生激活免疫系统的化学信号（细胞因子）。ILC家族的一员，ilc3，已经被发现在肠道中富集，在那里它们可以防止肠道细菌的入侵，并产生维持组织细胞健康的因子。目前还没有关于人类肾脏和膀胱中是否存在ILC3s的信息。我们对发现ILC3s在这些组织中是否重要很感兴趣，并进行了一些初步实验。令人兴奋的是，我们在小鼠和人的肾脏和膀胱中发现了ILC3s。这个项目的目的是找出他们到底在做什么，具体如下：1 . ILC3s在肾脏和膀胱中的位置以及它们是否位于其他免疫哨兵的附近。ILC3s在健康期间和对引起uti的细菌的反应中产生什么样的免疫信号分子（趋化因子和细胞因子）？我们可以使用小鼠模型和捐献的用于移植的人体组织，但不能使用。ILC3s如何在肾脏和膀胱中巡逻，以及它们是否与其他免疫细胞形成相互作用。为了回答这个问题，我们将使用一种特殊的显微镜和具有荧光标记的ILC3s的小鼠。我们已经开发了一种方案，使我们能够实时成像肾脏和膀胱中的细胞，因此我们可以开始研究控制它们运动的因素以及它们与其他免疫细胞的相互作用。是否尿路感染的结局和疾病严重程度受到ILC3s缺失的影响，使用由于ILC3s发育所需因子的遗传缺失而缺乏ILC3s的小鼠。阐明ILC3s的作用将有助于我们了解它们是否有助于清除肾道细菌的有益免疫反应。这将使我们能够利用它们的有用功能来开发更好的治疗策略，从而减少尿路感染的频率或与复发性感染相关的疤痕。从长远来看，这可以防止患者患上肾衰竭，并有助于延长肾脏移植的寿命，肾脏也可能因反复感染而受损。

项目成果

Mucosal IgG in inflammatory bowel disease - a question of (sub)class?

炎症性肠病中的粘膜 IgG——（亚）类问题？

• DOI: 10.17863/cam.43332
• 发表时间: 2020
• 作者: Castro-Dopico T

GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation.

GM-CSF 在肠道感染和炎症期间校准巨噬细胞防御和伤口愈合程序。

• DOI: 10.17863/cam.53966
• 发表时间: 2020
• 作者: Castro-Dopico T

B cell Fc? receptor IIb modulates atherosclerosis in male and female mice by controlling adaptive germinal center and innate B1-cell responses

B 细胞 Fc？

• DOI: 10.17863/cam.40120
• 发表时间: 2019
• 作者: Bagchi-Chakraborty J

Bromodomain Inhibitors Modulate Fc?R-Mediated Mononuclear Phagocyte Activation and Chemotaxis.

Bromodomain 抑制剂调节 Fc?R 介导的单核吞噬细胞激活和趋化性。

• DOI: 10.17863/cam.84831
• 发表时间: 2022
• 作者: Banham G

IgG and Fc? Receptors in Intestinal Immunity and Inflammation.

IgG 和 Fc？

• DOI: 10.17863/cam.38374
• 发表时间: 2019
• 作者: Castro-Dopico T