Background & Aims
Nociception is the neural process of encoding noxious stimuli and is conducted by specialised sensory neurons called nociceptors. Following tissue damage and inflammation, nociceptors commonly undergo sensitisation to encourage protective behaviours that promote healing. However, in a pathological setting inappropriate sensitisation can lead to the development of chronic pain disorders such as rheumatoid arthritis (RA). Interleukin (IL)-7 is a proinflammatory cytokine that shares a long-standing association with RA pathogenesis. Previous literature showcases clear correlations between IL-7 expression levels within the synovial fluid and RA disease activity (Pickens et al., 2011). Furthermore, subcutaneous administration of IL-7 leads to increased osteoclastogenesis and bone resorption (Miyaura et al., 1997). Yet, despite numerous investigations evidencing 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.
Methods
To investigate whether IL-7 induces pain in vivo, a single intraarticular injection of IL-7 was administered into the knee joint of mice, whereby pain-related behaviours were assessed for up to one week post injection. Additionally, in a complete Freund’s adjuvant (CFA) mouse model of joint inflammation, animals were treated with a monoclonal antibody against the IL-7 receptor (IL-7R) to determine any ameliorating effects on pain. To further explore how IL-7 may interact with sensory neurons at the cellular level, lumbar (L2-L5) dorsal root ganglia (DRG) neurons were dissociated and cultured. The response of these sensory neurons to IL-7 exposure was then characterised through a series of Ca2+ imaging and patch clamp electrophysiology experiments. Furthermore, co-culture with fibroblast-like synoviocytes (FLS) was also conducted and responses compared to results from DRG monocultures.
Results
We show that intraarticular administration of IL-7 induces joint inflammation and certain pain-related behavioural changes in mice, whereas inhibiting IL-7 signalling with an anti-IL-7R monoclonal antibody reduces inflammatory pain in the CFA mouse model of arthritis. In an in vitro setting, whilst we find that IL-7 does not directly activate DRG neurons, our results show that IL-7 can influence DRG neuron activity indirectly when sensory neurons are co-cultured with FLS, a cell type that expresses IL-7R, which may in part explain the in vivo effects of IL-7.
Conclusions
Taken together, these data begin to unearth the influence of IL-7 on joint pain at the of scale of both an individual and nociceptor. Additionally, the contribution of FLS towards these findings highlights the need to further study other cellular interactions in order to gain a more holistic understanding of the role of IL-7 in RA-associated joint pain.
References
Altawil, R. et al. (2016) Remaining Pain in Early Rheumatoid Arthritis Patients Treated With
Methotrexate, Arthritis Care and Research, 68(8), pp. 1061–1068. doi: 10.1002/acr.22790.
Miyaura, C. et al. (1997) Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: Similarity to estrogen deficiency, Proceedings of the National Academy of Sciences of the United States of America, 94(17), pp. 9360–9365. doi: 10.1073/pnas.94.17.9360.
Pickens, S. R. et al. (2011) Characterization of interleukin-7 and interleukin-7 receptor in the
pathogenesis of rheumatoid arthritis, Arthritis and Rheumatism, 63(10), pp. 2884–
2893. doi: 10.1002/art.30493.
Presenting Author
Helen Hilton
Poster Authors
Topics
- Models: Chronic Pain - Inflammatory