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

肾脏在清洁血液和控制身体水分平衡方面起着至关重要的作用。不幸的是，它们的功能可能会受到一些常见疾病的影响，这些疾病可能会危及生命，包括感染。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，甚至肾功能衰竭。人体的所有组织都有免疫系统的细胞。这些哨兵在组织中站岗，通过启动炎症反应来提醒身体注意感染。在肾脏，免疫哨兵对感染或组织损伤的反应决定了炎症的程度，这可能会影响细菌是否被清除，是否存在附带损害，最终影响肾脏功能是否恢复或形成疤痕。目前，我们还不完全了解人类肾脏和膀胱中存在什么类型的组织驻留免疫细胞，也不完全了解它们的确切功能。应对这一挑战将有助于我们开发更好的治疗影响肾脏的疾病，包括尿路感染。在过去的5年里，一个新的免疫细胞家族被发现，即天然淋巴样细胞(ILCs)。这些细胞充当组织哨兵，产生化学信号(细胞因子)来激活免疫系统。ILC家族中的一个成员ILC3s被发现富含在肠道中，在那里它们阻止来自肠道的细菌入侵，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ILC3的信息。我们有兴趣找出ILC3是否在这些组织中起重要作用，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ILC3。本项目的目的是找出它们到底在做什么，如下所示：1.ILC3在肾脏和膀胱中的位置，以及它们是否位于其他免疫标记附近。在健康和对引起尿路感染的细菌的反应中，ILC3产生了什么样的免疫信号分子(趋化因子和细胞因子)。我们可以使用已经捐赠用于移植的小鼠模型和人类组织，但不能使用。ILC3如何巡视肾脏和膀胱，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类型的显微镜和带有荧光标记的ILC3的小鼠。我们已经开发了一种方案，允许我们对肾脏和膀胱中的细胞进行实时成像，这样我们就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。UTI的结局和疾病严重程度是否受到ILC3缺失的影响，使用的是由于发育所需的一个因子的基因缺失而缺乏ILC3的小鼠。了解ILC3的工作原理将有助于我们了解它们是否有助于清除肾路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，以减少尿路感染或可能与反复感染相关的疤痕形成的频率。从长远来看，这可以防止患者患上肾衰竭，并有助于延长肾移植的寿命，而肾移植也可能因反复感染而受损。

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.