TRPC3 Antagonizes Pruritus in A Mouse Contact Dermatitis Model

Katherine Beattie , Haowu Jiang , Mayank Gautam , Mary K MacVittie , Barbara Miller , Minghong Ma , Qin Liu , Wenqin Luo 

Abstract

Contact dermatitis (CD), including allergic and irritant CD, are common dermatological diseases and characterized by an erythematous rash and severe itch. In this study, we investigated the function of TRPC3, a canonical TRP channel highly expressed in type 1 non-peptidergic (NP1) nociceptive primary afferents and other cell types, in a mouse CD model. Though TrpC3 null mice had little deficits in acute somatosensation, they showed significantly increased scratching with CD. In addition, TrpC3 null mice displayed no differences in mechanic and thermal hypersensitivity in an inflammatory pain model, suggesting that this channel preferentially functions to antagonize CD-induced itch. Using dorsal root ganglia (DRG) and pan-immune-specific TrpC3 conditional KO (CKO) mice, we determined that TrpC3 in DRG neurons, but not in immune cells, is required for this phenotype. Furthermore, the number of MRGPRD⁺ NP1 afferents in CD-affected DRGs is significantly reduced in TrpC3 mutant mice. Taken together, our results suggest that TrpC3 plays a critical role in NP1 afferents to cope with CD-induced excitotoxicity, and that degeneration of NP1 fibers may lead to an increased itch of CD. Our study identified a role of TrpC3 and NP1 afferents in CD pathology.

Keywords: Contact dermatitis; DRG; MRGPRD; TRPC3; non-peptidergic nociceptors; pruritus.

Reduced spontaneous itch in mouse models of cholestasis

Published in:- Scientific Reports (2021.03.17) IF~4.379

Jacqueline Langedijk, Ruth Bolier, Dagmar Tolenaars, Lysbeth ten Bloemendaal, Suzanne Duijst, Dirk de Waart, Ulrich Beuers, Piter Bosma & Ronald Oude Elferink

Abstract

Pruritus is one of the most distressing symptoms in cholestatic patients. Plasma autotaxin (ATX) activity correlates with the severity of pruritus in cholestatic patients, but the pathophysiology is unclear. To study pruritus in mice, we measured scratch activity in cholestatic Atp8b1 mutant mice, a model for Progressive Familial Intrahepatic Cholestasis type 1, and wild type mice (WT) with alphanaphthylisothiocyanate (ANIT)-induced cholestasis. To induce cholestasis, Atp8b1 mutant mice received a diet containing 0.1% cholic acid (CA) and WT mice were treated with ANIT. In these mice ATX was also overexpressed by transduction with AAV-ATX. Scratch activity was measured using an unbiased, electronic assay. Marked cholestasis was accomplished in both Atp8b1 mutant mice on a CA-supplemented diet and in ANIT-treatment in WT mice, but scratch activity was decreased rather than increased while plasma ATX activity was increased. Plasma ATX activity was further increased up to fivefold with AAV-ATX, but this did not induce scratch activity. In contrast to several reports two cholestatic mouse models did not display increased scratch activity as a measure of itch perception. Increasing plasma ATX activity by overexpression also did not lead to increased scratch activity in mice. This questions whether mice are suitable to study cholestatic itch.

TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch 

by Jenny Wilzopolski ^1,2,3,*, Manfred Kietzmann ¹, Santosh K. Mishra ², Holger Stark ⁴, Wolfgang Bäumer ^2,3 and Kristine Rossbach¹

¹Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany

²Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA

³Department of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany

⁴Institute of Pharmaceutical and Medical Chemistry, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany

^*Author to whom correspondence should be addressed. Academic Editors: Emanuela Masini, Laura Lucarini and Alessandro AlaimoBiomolecules2021, 11(8), 1166; https://doi.org/10.3390/biom11081166Received: 13 July 2021 / Revised: 31 July 2021 / Accepted: 4 August 2021 / Published: 6 August 2021(This article belongs to the Special Issue New Developments in Histamine Research)

Abstract: Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the trans- mission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.

Keywords: histamine; histamine H1 receptor; histamine H4 receptor; itch; signal transduction; TRPV1; TRPA1; dorsal root ganglion neurons (DRG); Ca2+-imaging