Evidence for a novel protective role of the vanilloid TRPV1 receptor in a cutaneous contact allergic dermatitis model

Abstract

The purpose of this study was to examine the involvement of the transient receptor potential vanilloid receptor 1 (TRPV1) in inflammatory processes observed in murine allergic contact dermatitis (ACD). Oxazolone-induced ACD evoked a significant ear swelling after 24–72 h. It was augmented in TRPV1 knockout mice at all time points and supported by histological analysis and measure of TNF-α. However, tissue swelling and cytokine generation was significantly reduced in both neurokinin 1 receptor and calcitonin gene-related peptide (CGRP) knockout mice. A protective involvement of the TRPV1 receptor was identified of contact dermatitis distinct from mechanisms involving the major pro-inflammatory neuropeptides.

Introduction

Contact dermatitis is a chronic allergic disorder characterised by skin inflammation and itching. It is a common disease with symptoms responsible for 20% of all work-related health problems reported to clinicians in the UK each year and is a major cause of loss of working days (Brown, 2004). Contact dermatitis can be induced by a multitude of irritants and/or allergens that are influenced by a range of environmental conditions. The concept that sensory nerves, comprising C and Aδ fibers, have the potential to modulate allergic contact dermatitis responses is established, although precise mechanisms have been difficult to define (Brain, 1997). The skin is heavily innervated by sensory nerve fibers which release pro-inflammatory neuropeptides, e.g., tachykinins and calcitonin gene-related peptide (CGRP) or anti-inflammatory peptide mediators, e.g., somatostatin and galanin. Raised levels of neuropeptides have been measured in the effector phase of allergic contact dermatitis (ACD) that is observed in man 72 h after challenge of sensitized skin and in murine models 24–48 h (Krasteva et al., 1999), although the mechanisms responsible for the stimulation of sensory nerves and release of neuropeptides are unclear.

Capsaicin, the active ingredient of hot peppers selectively excites and then desensitizes a major subpopulation of nociceptive sensory nerve fibers which contain the above mentioned sensory neuropeptides that are classified as “capsaicin-sensitive afferents” (Szolcsanyi, 1996). Recent studies have identified and cloned the receptor for capsaicin, first called VR-1 and now called TRPV1 (Caterina et al., 1997). The TRPV1 receptor is associated with a cation channel, which can be activated by noxious heat, protons, and vanilloids such as capsaicin (Caterina et al., 1997), or the ultra-potent agonist resiniferatoxin (RTX). There has been confirmation that this receptor is involved in mediating inflammatory hyperalgesia (Davis et al., 2000) either alone or in combination with other mediator pathways (Amadesi et al., 2004).

Substantial efforts have been made to elucidate the nature and physiological roles of endogenous ligands at TRPV1 receptors. Recently, several potential candidates have been identified from isolated cell studies such as anandamide (arachidonyl ethanolamide) (Di Marzo et al., 2002), N-arachinodyl-dopamine (NADA) (Huang et al., 2002), N-oleoyldopamine (OLDA) (Chu et al., 2003) or lipoxygenase products (Hwang et al., 2000), although their relative importance in vivo is unknown as yet. Sensory neuropeptides can be released from the capsaicin-sensitive nerve endings by TRPV1 receptor-mediated or TRPV1 receptor-independent mechanisms (Banvolgyi et al., 2004). The acute response to topical application of capsaicin in the mouse ear is characteristic of neurogenic inflammation, observed as increased blood flow and edema formation that is dependent on the release and actions of CGRP and substance P (Grant, 2002). However, the consequences of endogenous activation of the TRPV1 receptor in pathophysiological situations are less well-understood. Importantly, the activation of the TRPV1 receptor on sensory nerves by capsaicin or resiniferatoxin in rodent tissues is followed by depletion of sensory neuropeptides and desensitization of the TRPV1 receptor. This leads to a selective blockade of the function of the sensory neurogenic component, and recently resiniferatoxin pretreatment has been used to abolish the sensory neurogenic component in experimental models in laboratories including our own (Helyes et al., 2004).

The aim of the present study was to investigate whether the TRPV1 receptor plays a role in the pathogenesis of contact dermatitis. We have utilized an ear model of oxazolone-induced allergic contact dermatitis (ACD) and investigated responses in mice lacking the TRPV1 receptor or in mice pretreated with resiniferatoxin to block the TRPV1 sensory neurogenic component. The results reveal an involvement of the TRPV1 receptor, in that chemical or genetic deletion of the TRPV1 receptor led to an enhancement of the inflammatory response. Thus a critical but protective role of the TRPV1 receptor in this murine model of contact dermatitis is demonstrated.