Interleukin-17A is involved in mechanical hyperalgesia but not in the severity of murine antigen-induced arthritis

Matthias Ebbinghaus,Firas Subhi Salah,Martin Böttcher,Martin Böttcher,Hans-Georg Schaible,Gisela Segond Von Banchet,Mieczyslaw Gajda,Birgit Hoffmann,Gabriel Natura,Thomas Kamradt,Susanne Hensellek

doi:10.1038/s41598-017-10509-5

Matthias Ebbinghaus, Firas Subhi Salah + Show 9 more

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https://doi.org/10.1038/s41598-017-10509-5

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Abstract

Interleukin-17A (IL-17A) is considered an important pro-inflammatory cytokine but its importance in joint diseases such as rheumatoid arthritis (RA) is unclear. It has also been reported that IL-17A may induce pain but it is unclear whether pro-inflammatory and pro-nociceptive effects are linked. Here we studied in wild type (WT) and IL-17A knockout (IL-17AKO) mice inflammation and hyperalgesia in antigen-induced arthritis (AIA). We found that the severity and time course of AIA were indistinguishable in WT and IL-17AKO mice. Furthermore, the reduction of inflammation by sympathectomy, usually observed in WT mice, was preserved in IL-17AKO mice. Both findings suggest that IL-17A is redundant in AIA pathology. However, in the course of AIA IL-17AKO mice showed less mechanical hyperalgesia than WT mice indicating that IL-17A contributes to pain even if it is not crucial for arthritis pathology. In support for a role of IL-17A and other members of the IL-17 family in the generation of pain we found that sensory neurones in the dorsal root ganglia (DRG) express all IL-17 receptor subtypes. Furthermore, in isolated DRG neurones most IL-17 isoforms increased tetrodotoxin- (TTX-) resistant sodium currents which indicate a role of IL-17 members in inflammation-evoked sensitization of sensory nociceptive neurones.

Highlights

Interleukin-17A (IL-17A), before 2003 in the context of autoimmune diseases commonly only called IL-17, and five additional cytokines (IL-17B-F) form a family of closely related cytokines[1, 2]
IL-17A induces the release of chemokines and cytokines (IL-1β, IL-6, IL-8, RANKL, TNF), matrix metalloproteinases, nitric oxide and prostaglandin E2 from fibroblasts, osteoblasts, chondrocytes and macrophages, all cells involved in rheumatoid arthritis (RA) pathogenesis[9, 11,12,13,14]
We found previously that in the acute stage of murine antigen-induced arthritis (AIA) chemical sympathectomy strongly reduced the severity of inflammation and hyperalgesia[28]

Summary

Introduction

Interleukin-17A (IL-17A), before 2003 in the context of autoimmune diseases commonly only called IL-17, and five additional cytokines (IL-17B-F) form a family of closely related cytokines[1, 2]. In the model of antigen-induced arthritis (AIA), IL-17A knock-out (IL-17AKO) mice showed reduced swelling at the very beginning[20]. The severity of AIA in wild type (WT) mice was only weakly attenuated by blocking IL-1721. Because pain is a major symptom of arthritis, the neuronal effects of IL-17 deserve further attention. In several arthritis models sympathectomy significantly attenuated the severity of inflammation[26, 27]. We found previously that in the acute stage of murine AIA chemical sympathectomy strongly reduced the severity of inflammation and hyperalgesia[28]. Sympathectomised C57BL/6 WT mice showed decreased amounts of IL-2 and a striking reduction of IL-17A produced by lymphocytes in vitro[28] raising the hypothesis that the anti-inflammatory effect of sympathectomy depends mechanistically on IL-17A

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