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

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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.