Fibroblasts as key drivers of persistent pain in inflammatory arthritis

Chronic pain is a frequent and disabling facet of many immune-mediated diseases, including inflammatory arthritis. A particularly puzzling phenomenon is that during disease-modifying treatments, pain can become uncoupled from inflammation. This results in minimal disease activity but persistent pain for the individuals affected. Pain in the absence of overt inflammation is frequently ascribed to dysfunction of spinal cord and cortical pain circuits. Conversely, pain during inflammation is seen as a natural consequence of immune cells driving peripheral neuron hyperactivity. This perspective, however, neglects the potential of tissue-resident stromal cells, like fibroblasts, to drive pain in the absence of inflammation. Our overarching hypothesis is that fibroblasts are key drivers of persistent pain in inflammatory disease. Using rheumatoid arthritis as a model, we will unite expertise across traditionally distinct disciplines to: - Demonstrate that human sub-lining synovial fibroblasts are a prominent source of pro-algesic mediators and can induce neurite outgrowth. - Demonstrate that sub-lining fibroblasts drive neuronal hyper-excitability and pain behaviours. - Find novel analgesic targets by blocking fibroblast-derived pro-algesic mediators or fibroblast sub-populations. Our research will provide much-needed interdisciplinary insights into the basic principles of how peripheral nerves and fibroblasts interact in painful disease and accelerate the urgent search for more effective analgesics.