The role of interleukin-17 and interferon-gamma in the generation of arthritic pain
Final Report Abstract
The neutralization of proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) has dramatically improved the therapy of rheumatoid arthritis. Often the disease progression can be stopped and arthritic pain may be abolished or attenuated. However, significant problems remain. In a significant number of patients TNF neutralization does not cause remission. Moreover, even if the disease progression is stopped, pain may persist. One possible reason for such failures could be that other proinflammatory cytokines are critically involved in the disease progression and/or the pain generation. In this project we explored the role of interleukin-17 (IL-17) and interferongamma (IFN-gamma) in the generation of arthritic pain. Both cytokines are part of the cytokine network involved in the pathogenesis of rheumatoid arthritis and related diseases. We found that IL-17 is a potent pain mediator. A large proportion of the nociceptive sensory neurons express receptors for members of the IL-17 family such as IL-17A. Injection of IL-17A into a normal joint causes a persistent increase of the responsiveness of the sensory neurons to mechanical stimuli similar as an inflammation. In isolated nociceptive sensory neurons IL-17A and other IL-17 family members cause an increase of excitability and sodium currents, typical features of pain sensitization. Neutralization of IL-17A by antibodies attenuates inflammation-evoked mechanical hyperalgesia (pain evoked by mechanical stimuli). Two aspects are particulary noteworthy. First, in the model of antigen-induced arthritis (AIA) IL-17A knockout mice did not show a reduction of the arthritis (corresponding to similar findings in human rheumatoid arthritis) but mechanical hyperalgesia was significantly reduced. Thus, even if IL-17A is not critical for the inflammatory process, it could be an important mediator of arthritic pain. Second, neutralization of IL-17A or IL-17A deficiency only reduced mechanical but not thermal hyperalgesia (pain evoked by thermal stimulation), suggesting that IL-17 targets molecules in sensory neurons which are particularly involved in the transduction of mechanical stimuli. We found that TRPV4 ion channels play an important role in the response of sensory neurons to mechanical stimuli. IL-17A upregulates the expression of TRPV4 ion channels whereas it does not upregulate the expression of TRPV1 ion channels which are involved in the response of sensory neurons to painful thermal stimuli. Interferon-gamma (IFN-gamma) has an important role in adaptive immunity as a major effector cytokine of Th1 cell immunity, and it activates macrophages which are involved in pain generation. The hypothesis was, therefore, that IFN-gamma would cause pain. We found that many nociceptive sensory express receptors for IFN-gamma, and that short term application of IFN-gamma increases the excitability of sensory neurons. Surprisingly, however, in vivo IFN-gamma reduced the responses of sensory neurons to mechanical stimuli. In the AIA model IFN-gamma knockout mice exhibited stronger mechanical hyperalgesia than wild type mice. Thus, under inflammatory conditions IFN-gamma seems to be antinociceptive. When IL-17A and IFN-gamma are coapplied, IFN-gamma wins, i.e. the pain producing effect of IL-17A is attenuated or even abolished. These findings have several interesting implications. First, the antinociceptive effect of IFN-gamma may explain why many autoimmune processes involving Th1 cells do not cause hyperalgesia or pain and remain unrecognized although they have the potential to induce inflammation. Second, the presence of IFN-gamma during the disease process may determine to which extent IL-17A and possibly other cytokines cause pain. Further studies should clarify two questions. First, which cellular mechanisms cause the switch of the action of IFN-gamma from pro- to antinociceptive? Second, does the level of IFN-gamma significantly influence the clinical outcome of cytokine neutralization with respect to inflammation and pain?
Publications
- Interleukin-17A is involved in mechanical hyperalgesia but not in the severity of murine antigen-induced arthritis. Scientific Reports 2017;7:10334
Ebbinghaus M, Natura G, Segond von Banchet G, Hensellek S, Böttcher M, Hoffmann B, Salah FS, Gajda M, Kamradt T, Schaible H-G.
(See online at https://doi.org/10.1038/s41598-017-10509-5) - The contribution of inflammation and bone destruction to pain in arthritis - a study in murine glucose-6-phosphate isomerase (G6PI)-induced arthritis. Arthritis Rheumatol 2019;71:2016-2026
Ebbinghaus M, Müller S, Segond von Banchet G, Eitner A, Wank I, Hess A, Hilger I, Kamradt T, Schaible H-G.
(See online at https://doi.org/10.1002/art.41051) - Transient Receptor Potential vanilloid 4 ion channel in C-fibres is involved in mechanonociception of the normal and inflamed joint. Scientific Reports 2019; 9,10928
Richter F, Segond von Banchet G, Schaible H-G
(See online at https://doi.org/10.1038/s41598-019-47342-x)
