Sensory TRP channels contribute differentially to skin inflammation and persistent itch

Abstract

Although both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways. Here we show that both TRPA1 and TRPV1 channels are required for generating spontaneous scratching in a mouse model of ACD induced by squaric acid dibutylester (SADBE), a small molecule hapten, through directly promoting the excitability of pruriceptors. TRPV1 but not TRPA1 channels protect the skin inflammation, as genetic ablation of TRPV1 function or pharmacological ablation of TRPV1-positive sensory nerves promotes cutaneous inflammation in the SADBE-induced ACD. Our results demonstrate that persistent itch and inflammation are mediated by distinct cellular and molecular mechanisms in a mouse model of ACD. Identification of distinct roles of TRPA1 and TRPV1 in regulating itch and inflammation may provide new insights into the pathophysiology and treatment of chronic itch and inflammation in ACD patients.

Molecular and Functional Neuroscience in Immunity

“…In addition to sensing immune molecules and pathogens, afferent neurons actively modulate immune responses and inflammation, as demonstrated in experimental IBD (46), arthritis (48), asthma (60), skin inflammation and chronic itch (61, 62), and bacterial infection (3, 42). Sensory neurons release substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and other molecules interacting with the endothelium, neutrophils, macrophages, and other immune cells in the vicinity of axonal terminals (3, 42, 63) (Figure 2).…”

Calcium imaging of primary canine sensory neurons: Small‐diameter neurons responsive to pruritogens and algogens

“…Current research suggests that TRPV1 is involved in itch, and therefore, activation of these neurons may still confer itch transmission (Feng et al, ; Fukuyama, Ganchingco, Mishra, et al, ). Additionally, TRPA1 was shown to be necessary for itch transmission (Feng et al, ). Furthermore, substance P was shown to be biologically active on a pruriceptor and the NK‐1 receptor involved in itch transmission (Akiyama et al, , ; Azimi et al, ).…”

“…However, similar to previous studies there is a significant proportion of neurons responsive to a pruritogen and capsaicin concluding concurrent expression of pruriceptors and TRPV1 on these peripheral sensory neurons, demonstrating there are not separate pain and itch sensory neurons (Akiyama et al, 2010a(Akiyama et al, , 2012Akiyama, Merrill, Carstens, & Carstens, 2009;Akiyama, Tominaga, Takamori, Carstens, & Carstens, 2014;Gold, Dastmalchi, & Levine, 1996;Lu, Zhang, & Gold, 2006;Nakagawa & Hiura, 2013). Current research suggests that TRPV1 is involved in itch, and therefore, activation of these neurons may still confer itch transmission (Feng et al, 2017;Fukuyama, Ganchingco, Mishra, et al, 2017b). Additionally, TRPA1 was shown to be necessary for itch transmission (Feng et al, 2017).…”

“…This study aims to incorporate both itch and pain transmission by exposure of sensory neurons to agonists that are determined to be either pruritogenic through histamine‐dependent pathways (histamine) and histamine‐independent pathways (chloroquine, bovine adrenal medulla peptide, canine protease‐activated receptor 2 activating peptide, compound 48/80, and 5‐hydroxytryptamine) or algogenic (substance P, allyl isothiocyanate, capsaicin) (Akiyama & Carstens, ; Akiyama, Carstens, & Carstens, ; Davidson et al, ; Han et al, ; Metz, Grundmann, & Stander, ; Nakagawa & Hiura, ; Ohtori et al, ; Paus et al, ; Schemann et al, ; Valtcheva et al, ). The distinction of these algogenic substances only involved in pain has become less clear as current research has also shown their receptors associated with inducing itch and an off‐target activation of a pruriceptor by substance P (Akiyama et al, ; Azimi et al, ; Feng et al, ; Fukuyama, Ganchingco, Mishra, et al, ; Ständer & Yosipovitch, ). Receptors for these agonists are mainly G protein‐coupled receptors, including tachykinin receptor‐1, histamine‐1 receptor, sensory neuron receptor, protease‐activated receptor 2, and mas‐related G protein‐coupled receptors (Mrgprs).…”

Treatments for chronic pruritus outside of the box

“…Cytokine receptors directly associated with itch are the IL‐4 receptor α (IL‐4R α), IL‐31 receptor, oncostatin M receptor (OSMR) and the thymic stromal lymphopoietin (TSLP) receptor . Additionally, some ion channels such as voltage‐gated sodium channel (NaV1.7) and the transient receptor potential (TRP) channels TrpV1 and TrpA1 have been shown to be involved in the transmission of itch signals …”