Title: Lymphotactin in arthritis pain
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is the most common form of arthritis and is the fastest growing cause of chronic pain worldwide. Further research is urgently needed to improve the understanding of OA pain and develop improved treatments. We propose to investigate the role of the chemokine lymphotactin (XCL1) in OA pain. XCL1 has an established role in the immune system. Produced in response to infection and inflammation, it induces a chemotactic response through binding to its receptor (XCR1). Recent research now indicates a role for the XCL1–XCR1 axis in pain processing. Evidence from animal models supports a role for this chemokine axis in pain of neuropathic origin, induced by nerve injury and diabetic neuropathy, and suggests this axis may provide a new target for analgesics. The presence of XCL1 and XCR1 in human joint tissue in rheumatoid arthritis (RA) is established, with evidence of a functional role for XCL1, aggravating disease in animal models of RA. The role of XCL1 and XCR1 in arthritis-associated pain has not been investigated. OA pain has both neuropathic and nociceptive components. Our recent work shows that XCR1 is present in injured human nerves and in nerve fibres within inflamed human tooth pulp from patients with dental pain, suggesting that the XCL1–XCR1 pathway may be important in pain arising through both neuropathic and inflammatory mechanisms in man. We have now shown that XCR1 is present in nerves in human OA joints, and we hypothesise that XCL1 and XCR1 contribute to OA pain. This proposal aims to investigate the contribution of lymphotactin to OA pain and determine the potential of the XCL1–XCR1 axis as an analgesic target using clinical samples and preclinical models. Aims and brief experimental plan: To establish whether there is a link between the expression of XCL1 and XCR1 in human OA joint tissues and the presence of pain. Using a repository of human joint tissues (paired with extensive clinical data) that permits the detection of synovial factors associated with both OA symptoms and pathology, comparisons will be made between expression in symptomatic (from patients with pain) and asymptomatic (no pain) joints. To consolidate the evidence for a link between the expression of XCL1 and XCR1, and OA pain behaviour in an animal model. Expression in the knee joint and/or spinal cord will be compared between a model of OA and sham control. Associations between expression levels and OA pain behaviour will be identified. To determine the impact of neutralisation of XCL1 on OA pain behaviour. Using the same model of OA pain, the impact of XCL1 neutralisation will be determined to explore the relationship between activation of the XCL1–XCR1 axis and OA pain. This proposal aligns with the Versus Arthritis research roadmap for pain priority area: ‘Advancing our understanding of the complexity of musculoskeletal pain, including identifying underlying pain mechanisms which support the development of new treatments’; and with the strategic areas of focus: to ‘Deliver impactful research into prevention, treatment and cure that transforms people’s lives’.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL