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？

• 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

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.

尽管动物模型已用于研究衰老期间免疫下降的机制，但寿命和物种特定差异的差异是动物与人之间的直接比较。此外，大多数人类研究都是对从血液中分离出来的白细胞进行的，这些白细胞可能无法反映在组织中免疫反应期间发生的事件，类似于说在高速公路上旅行的人代表了居住在高速公路上的大城市的人们。我们开发了一种在免疫反应期间研究人体组织中的白细胞的新方法。通过这些新方法，我们试图理解为什么年长的人对皮肤中应该免疫的病原体反应不佳，例如水痘病毒。这也可以解释为什么老年人会患上更多的皮肤癌和更多的皮肤感染。在先前的研究中，我们提出了一个令人惊讶的发现，老年人对水痘病毒的反应减少并不是由于与血液或皮肤中的年轻受试者相比，识别该病毒的白细胞数量减少。相反，这种反应减少是由于皮肤环境本身的变化所致，我们确定了更多背景炎症。我们在这项先前的研究中所做的是使用葛兰素史密斯 - 克林（GSK）的抗炎药减少旧志愿者的炎症，以查看这是否可以增强其对水痘病毒的皮肤的反应。简而言之，我们能够做到这一点，并且已经发表了这项工作。但是，关键问题仍未得到答复，包括确定炎症的来源，即皮肤中哪些细胞会产生？哪些细胞分泌蛋白质将炎症性白细胞（称为单核细胞）募集到皮肤上？最后，这些单核细胞如何有助于抑制衰老期间免疫反应？它们是单独或与其他细胞类型一起工作的吗？我们将把单个细胞从皮肤中取出，并查看其基因表达，以查看哪种细胞类型会产生炎症蛋白。我们将与剑桥大学的Menna Clatworthy教授一起进行这一研究，他已经使用这些技术对人体组织进行了极为重要的研究。我们还将确定哪些细胞分泌从血液中吸引炎性单核细胞到老年受试者皮肤的分子。与纽卡斯尔的Muzlifah Haniffa教授合作，我们将能够开始生成来自老年人不同皮肤细胞的基因组图，以与她已经分析过的年轻人进行比较。此外，与克里斯·巴克利（Chris Buckley）教授合作，他是类风湿关节炎患者炎症专家，我们将研究是否涉及皮肤中称为成纤维细胞的细胞，例如关节中。我们的初步结果提出了这种可能性，我们设想不同细胞类型之间可能的相互作用，以诱导我们在老年人皮肤中观察到的炎症。这将通过我们将使用Clatworthy教授执行的单个单元RNASEQ分析来解决。下一个问题是炎症如何阻止皮肤中居民白细胞的功能。我们将测试这是否是由于造成罪魁祸首的分泌因子的直接抑制作用，如果炎症会使其他细胞触发刹车以抑制免疫力，或者炎症在“官兵警察”中呼唤“被称为调节性细胞”，以使皮肤中的所有物体平静下来。最后，我们将使用先前研究中生成的生物银行样品来探测如何抑制旧作品的炎症 - 可以防止炎症单核细胞的募集吗？防止产生抑制细胞或停止不同细胞类型之间的相互作用，从而破坏它们之间的协同作用，从而释放出炎症的火力。

项目成果

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

• DOI: 10.1016/j.ccell.2023.05.004
• 发表时间: 2023-07-10
• 期刊: CANCER CELL
• 影响因子: 50.3
• 作者: Haston, Scott;Gonzalez-Gualda, Estela;Martinez-Barbera, Juan Pedro
• 通讯作者: Martinez-Barbera, Juan Pedro

Senescent T cells: Beneficial and detrimental roles

• DOI: 10.1111/imr.13206
• 发表时间: 2023-04-25
• 期刊: IMMUNOLOGICAL REVIEWS
• 影响因子: 8.7
• 作者: Laphanuwat，Phatthamon;Gomes，Daniel Claudio Oliveira;Akbar，Arne N.
• 通讯作者: Akbar，Arne N.