Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons.

Éva Borbély,Attila Mócsai,Éva Szőke,Krisztina Pohóczky,Bálint Botz,Zsuzsanna Helyes,Alexandra Berger,Maja Payrits,Ágnes Hunyady

doi:10.3389/fphar.2020.594479

Abstract

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.

Highlights

Rheumatoid arthritis (RA) is the most common autoimmune disorder of the joints characterized by chronic inflammation and severe pain
Paw edema developed by the 3rd day of the experiment (43.8 ± 7.2% in wild type controls (WT)), and spontaneously resolved by 2 weeks after serum administration with significantly milder edema seen in the preprotachykinin-4 gene (Tac4)−/− mice (Figure 1C)
This is likely to be mediated by direct activation of primary sensory neurons via neurokinin-1 receptor (NK1R)-independent, pertussis toxin (PTX)-insensitive, but extracellular Ca2+dependent mechanism

Summary

INTRODUCTION

Rheumatoid arthritis (RA) is the most common autoimmune disorder of the joints characterized by chronic inflammation and severe pain. The joints are densely innervated by capsaicin-sensitive peptidergic sensory nerves (Donaldson et al, 1995) expressing, among others, the transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels activated by a broad range of inflammatory mediators (Pinho-Ribeiro et al, 2017). These nerves play an important role in complex neurovascular-immune interactions resulting in chronic pain (Sun and Dai, 2018). Tachykinins are a family of neuropeptides that have been shown to play important roles in immune mechanisms, inflammatory vascular changes and pain (Onaga, 2014). The present work focused on investigating the involvement of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain, nociceptive sensory neurons and the molecular mechanism of action

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT