How does blocking inflammation enhance human cutaneous immunity during ageing in vivo?

阻断炎症如何增强体内衰老过程中的人体皮肤免疫力？

基本信息

批准号：
MR/T030534/1
负责人：
Arne Akbar
金额：
$ 109.01万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT030534%2F1
关键词：
How does blocking inflammation enhance

项目摘要

Although animal models have been used to investigate mechanisms for immune decline during ageing, differences in lifespan and species specific differences prelude direct comparison between animals and humans. Furthermore, most human studies are conducted on white cells isolated from the blood that may not reflect on events that take place during an immune response in the tissues, akin to saying that people travelling on a motorway are representative of the people living in big cities served by the motorway. We developed a new way of investigating white cells in human tissues during an immune response. With these new methods we are trying to understand why older humans respond badly to pathogens in the skin that they should be immune to, like the chickenpox virus. This may also explain why older individuals get more skin cancer and also more skin infections. In a previous study we made a rather surprising finding that the reduced response to the chickenpox virus in old people was not due to a decrease in the number of white cells that recognize this virus as compared to young subjects in either the blood or the skin. Instead this decreased response was due to changes in the skin environment itself, where we identified more background inflammation. What we did in this previous study was to reduce the inflammation in old volunteers, using an anti-inflammatory drug from Glaxo-Smith-Kline (GSK) to see if this could enhance their response in the skin to the chickenpox virus. In a nutshell, we were able to do so and we have published this work. However key questions remained unanswered including identifying where the inflammation was coming from in the first place i.e. which cells in the skin were making it? Which cells secreted proteins to recruit inflammatory white blood cells, called monocytes, to the skin? Finally how do these monocytes contribute to the inhibition of the immune response during ageing? Do they work alone or together with other cell types?We will take individual cells out of the skin and look at their gene expression to see which cell type makes the inflammatory proteins. We will do this part of the study with Professor Menna Clatworthy in Cambridge University who has already performed extremely important studies on human tissue using these techniques. We will also determine which cells secrete the molecules that attract inflammatory monocytes from the blood into the skin of older subjects. In collaboration with Professor Muzlifah Haniffa in Newcastle we will be able to begin to generate a genomic map of different skin cells from old people for comparison with young individuals that she has already analysed. Furthermore in collaboration with Prof. Chris Buckley who is an expert on inflammation in joints in patient with Rheumatoid Arthritis, we will investigate if cells called fibroblasts in the skin are involved, like they are in the joints. This possibility is suggested by our preliminary results and we envisage possible interactions between different cell types to induce the inflammation we observe in the skin of older humans. This will be addressed with the single cell RNAseq analyses that we will perform with Prof. Clatworthy. The next question is how the inflammation blocks the function of the resident white cells in the skin. We will test if it is due to a direct inhibitory effect of secreted factors from the culprit cell, if the inflammation makes other cells turn on the brakes to inhibit immunity or if the inflammation calls in the "military police" known as regulatory cells that calms everything down in the skin. Finally we will used bio-banked samples that we generated in a previous study to probe how inhibiting inflammation in the old works -does it prevent recruitment of inflammatory monocytes? Prevent the generation of inhibitory cells or stop the interaction between different cell types, breaking the synergy between them and thus puts out the fire of inflammation.

尽管动物模型已被用来研究衰老过程中免疫衰退的机制，但寿命的差异和物种特异性的差异阻碍了动物和人类之间的直接比较。此外，大多数人类研究都是针对从血液中分离出的白细胞进行的，这可能无法反映组织中免疫反应期间发生的事件，类似于说在高速公路上行驶的人代表了生活在大城市的人们通过高速公路。我们开发了一种研究免疫反应期间人体组织中白细胞的新方法。通过这些新方法，我们试图了解为什么老年人对皮肤中本应免疫的病原体（如水痘病毒）反应不良。这也可以解释为什么老年人患皮肤癌和皮肤感染的比例更高。在之前的一项研究中，我们得出了一个相当令人惊讶的发现，即老年人对水痘病毒的反应减弱并不是因为与年轻人相比，血液或皮肤中识别这种病毒的白细胞数量减少。相反，这种反应下降是由于皮肤环境本身的变化，我们发现了更多的背景炎症。我们在之前的研究中所做的是使用葛兰素史克 (GSK) 的抗炎药物来减少老年志愿者的炎症，看看这是否可以增强他们皮肤对水痘病毒的反应。简而言之，我们能够做到这一点，并且我们已经发表了这项工作。然而，关键问题仍未得到解答，包括首先确定炎症从何而来，即皮肤中的哪些细胞产生炎症？哪些细胞分泌蛋白质将炎症白细胞（称为单核细胞）招募到皮肤？最后，这些单核细胞如何抑制衰老过程中的免疫反应？它们是单独起作用还是与其他细胞类型一起起作用？我们将从皮肤中取出单个细胞并观察它们的基因表达，以了解哪种细胞类型产生炎症蛋白。我们将与剑桥大学的 Menna Clatworthy 教授一起完成这部分研究，他已经使用这些技术对人体组织进行了极其重要的研究。我们还将确定哪些细胞分泌分子，将炎症单核细胞从血液吸引到老年受试者的皮肤中。通过与纽卡斯尔的 Muzlifah Haniffa 教授合作，我们将能够开始生成老年人不同皮肤细胞的基因组图谱，以便与她已经分析过的年轻人进行比较。此外，我们将与类风湿关节炎患者关节炎症专家 Chris Buckley 教授合作，研究皮肤中称为成纤维细胞的细胞是否参与其中，就像它们在关节中一样。我们的初步结果表明了这种可能性，并且我们设想不同细胞类型之间可能存在相互作用，从而诱发我们在老年人皮肤中观察到的炎症。我们将与 Clatworthy 教授一起进行单细胞 RNAseq 分析来解决这个问题。下一个问题是炎症如何阻碍皮肤中常驻白细胞的功能。我们将测试是否是罪魁祸首细胞分泌因子的直接抑制作用，炎症是否使其他细胞踩刹车抑制免疫，或者炎症是否召唤了被称为调节细胞的“军警”来镇静。一切都深入皮肤。最后，我们将使用我们在之前的研究中生成的生物库样本来探讨抑制旧炎症的作用——它是否可以阻止炎症单核细胞的募集？阻止抑制性细胞的产生或阻止不同细胞类型之间的相互作用，打破它们之间的协同作用，从而扑灭炎症之火。