Glial cells—the support cells that wrap around nerve fibres—are largely unstudied in the inflamed joints of people with rheumatoid arthritis, and this fellowship aims to find out whether they actively drive joint damage and pain. Rheumatoid arthritis affects 1% of the population and causes an estimated 2.43 million years of living with disability globally. Even with modern treatments, up to 40% of patients do not respond to any available therapy. Recent work has identified specific cell types in the synovium—the membrane lining the joints—that are linked to either remission or worsening inflammation. But glial cells, which are known to be present there, have been largely ignored. Outside the joint, glial cells can secrete factors that attract immune cells and present antigens to them, suggesting they may play a pro-inflammatory role in arthritis. This is fundamental science: the goal is to characterise these cells in human and mouse synovium using advanced imaging and single-cell sequencing, then test whether removing them alters inflammation in mice. If glial cells prove to be active contributors to joint inflammation, they could become new therapeutic targets for the 40% of patients who currently have no effective treatment. The work may also reveal unexpected roles for glial cells in pain generation, with relevance beyond arthritis to other inflammatory diseases.
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Rheumatoid arthritis (RA) is an immune mediated inflammatory disease affecting 1% of the population [1]. It is a major cause of disability as it can cause joint damage and pain, and the Global Disease Burden Study estimated it to cause 2.43 million years of living with disability globally[2]. Despite the use of biological and targeted therapies which have undoubtedly revolutionised the treatment of RA; there still remains a large unmet clinical need with up to 40% of patients not responding to all current treatments [3]. The synovium which is a membrane that lines our joints becomes thickened and inflamed in RA[4]. Recent advances in technology have enabled us to study the synovium at a cellular level and have led to the identification of important cell types such as the Mer tyrosine kinase (MerTK)+CD206+ macrophages [5] which are associated with remission of RA and the NOTCH3+ fibroblasts[6] which are associated with worsening inflammation. Importantly, these cell types may act as therapeutic targets in the future. The synovium is known to be innervated by the peripheral nervous system and peripheral nerve associated glial cells (also known as Schwann cells) [7, 8]. Peripheral glial cells are mostly known for providing trophic support to nerve fibres[9]. However, recent evidence has demonstrated their diverse functionality and role in immunity, tissue repair [10] and nerve regeneration [9]. They are able to secrete factors that attract immune cells [11] as well as facilitate the immune response by presenting antigen to other immune cells [12] . Although glial cells are known to be present in the synovium [7, 8], they are not well characterised. Based on current literature; we hypothesize that they have a pro-inflammatory role in the synovium in RA. Aims and objectives: The aim of this fellowship is to characterise glial cells in the synovium of patients with arthritis and gain an insight into their functionality. To achieve this, synovium from patients with arthritis and genetically modified mice with arthritis will be used. Advanced imaging techniques will identify these cells and study their architecture and cellular microenvironment in the mouse and human synovium in health and inflammation. Advanced sequencing techniques will also be used to study these cells individually to determine how they change with inflammation and understand their interaction with other cell types. Finally, glial cells will be ablated in the joint of genetically modified mice with arthritis to determine how this affects inflammation. Potential applications and benefits: This work will improve our understanding of the cellular composition of the synovium in RA and help us understand whether glial cells contribute to joint damage and inflammation. This may lead to the identification of new therapeutic targets which will benefit patients with RA. Characterisation of glial cells in the synovium may also uncover new roles of glial cells in the synovium such as in pain generation and will also help other scientists study the role of these important cells in other diseases.
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