Abstract
Innervation of the joint with thinly myelinated and unmyelinated sensory nerve fibres is crucial for the occurrence of joint pain. During inflammation in the joint, sensory fibres show changes in the expression of receptors that are important for the activation and sensitization of the neurones and the generation of joint pain. We recently reported that both neurokinin 1 receptors and bradykinin 2 receptors are upregulated in dorsal root ganglion (DRG) neurones (the cell bodies of sensory fibres) in the course of acute and chronic antigen-induced arthritis in the rat. In this study, we begin to address mechanisms of the interaction between fibroblast-like synovial (FLS) cells and sensory neurones by establishing a co-culture system of FLS cells and DRG neurones. The proportion of DRG neurones expressing neurokinin 1 receptor-like immunoreactivity was not altered in the co-culture with FLS cells from normal joints but was significantly upregulated using FLS cells from knee joints of rats with antigen-induced arthritis. The proportion of DRG neurones expressing bradykinin 2 receptors was slightly upregulated in the presence of FLS cells from normal joints but upregulation was more pronounced in DRG neurones co-cultured with FLS cells from acutely inflamed joints. In addition, the expression of the transient receptor potential V1 (TRPV1) receptor, which is involved in inflammation-evoked thermal hyperalgesia, was mainly upregulated by co-culturing DRG neurones with FLS cells from chronically inflamed joints. Upregulation of neurokinin 1 receptors but not of bradykinin 2 and TRPV1 receptors was also observed when only the supernatant of FLS cells from acutely inflamed joint was added to DRG neurones. Addition of indomethacin to co-cultures inhibited the effect of FLS cells from acutely inflamed joints on neurokinin 1 receptor expression, suggesting an important role for prostaglandins. Collectively, these data show that FLS cells are able to induce an upregulation of pain-related receptors in sensory neurones and, thus, they could contribute to the generation of joint pain. Importantly, the influence of FLS cells on DRG neurones is dependent on their state of activity, and soluble factors as well as direct cellular contacts are crucial for their interaction with neurones.
Highlights
The inflammatory response in organs is produced by numerous inflammatory cell types
dorsal root ganglion (DRG) neurones that showed strong neurone-specific enolase (NSE)-like immunoreactivity (IR) were dispersed as single cells or small cell clusters on the fibroblast-like synovial (FLS) cell layer (Figure 1b, neurones are labelled with stars)
The present study addresses the regulation of receptors in DRG neurones that are involved in the generation of inflammatory pain and hyperalgesia
Summary
The inflammatory response in organs is produced by numerous inflammatory cell types. These cell types communicate with each other in order to develop an appropriate inflammatory reaction. A large amount of information on the mechanisms of interaction of different inflammatory cells has been obtained from co-culture systems of different cell types, such as T cells and monocytes [1,2,3], T cells and endothelial cells [4], T cells and fibroblasts [5,6,7], monocytes and fibroblasts [8,9], and macrophages and fibroblasts [10,11,12] These data have established the importance of both cell-cell contacts and mediators for the production of the inflammatory activity. A first report appeared on the influence of neurones in the central nervous system on T cells and the potential role of neurone-T cell interactions on experimental autoimmune encephalomyelitis [17]
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