Establishing the role of interleukin-7 in joint pain: insights into neuronal-non-neuronal interactions in arthritis

Nociception is the neural process of encoding noxious stimuli, commonly associated with pain perception. As part of their physiological role, nociceptive neurons commonly undergo sensitisation following tissue damage and inflammation to encourage protective behaviours to promote healing within an individual. However, in a pathological setting inappropriate sensitisation can contribute to chronic pain in disorders such as rheumatoid arthritis (RA). Interleukin (IL)-7 is a proinflammatory cytokine that shares a long-standing association with RA pathogenesis. However, despite numerous investigations demonstrating the role of IL-7 in RA joint damage, the potential impact IL-7 has on RA-associated joint pain is yet to be explored. Here, I show that IL-7 is unable to directly activate dorsal root ganglia (DRG) sensory neurons, thus prompting an investigation into potential indirect mechanisms of DRG activation, induced by IL-7. While IL-7 did not appear to activate CD4+ T cells in vitro, it did promote the bone resorbing activity of osteoclasts. However, culture medium from IL-7 stimulated osteoclasts was not found to alter sensory neuron excitability. On the other hand, when DRG neurons were co-cultured with fibroblast-like synoviocytes (FLS), IL-7 stimulation led to a striking activation of DRG neurons. Subsequently, I identified a selection of pro-inflammatory mediators which may underlie this cell-cell interaction and ultimately help promote nociceptive signalling. To investigate whether IL-7 induces pain in vivo, a single intraarticular injection of IL-7 was administered into the knee joint of mice and was observed to induce joint inflammation and certain pain-related behavioural deficits in mice. Additionally, therapeutic intervention, by administering an anti-IL-7 receptor monoclonal antibody that functions as an antagonist, was found to reduce both certain pain-related behaviours and associated pathology in complete Freund’s adjuvant (CFA) and monosodium iodoacetate (MIA) mouse models of arthritis. In conclusion, this work has begun to unearth the complex mechanisms by which IL-7 may contribute to joint pain.