Itching in a trichophytin contact dermatitis mouse model and the antipruritic effect of antifungal agents

Clin Exp Dermatol. 2019 Jun;44(4):381-389. doi: 10.1111/ced.13719. Epub 2018 Sep 6.

Abstract

Background: Tinea is an infectious disease by dermatophytes, of which Trichophyton species accounts for the overwhelming majority of case. Tinea often causes itching with inflammation. In terms of pruritus by fungal infection, however, tinea has not been investigated sufficiently to date.

Aim: To evaluate itch caused by Trichophyton infection and the effect of antifungal agents on the infection, by measuring scratch behaviour and profiles of inflammatory cytokines and chemokines.

Methods: We used a previously established mouse model of contact hypersensitivity induced by trichophytin, a crude extract from Trichophyton mentagrophytes. Scratching behaviour was recorded using a counting device that measured an electric current induced in a coil by movement of magnets that had been inserted into the hind paws of each animal. We investigated expression of various genes in lesional skin of mice and in normal human epidermal keratinocytes. We also investigated the antipruritic effects of the corticosteroid dexamethasone (DEX) and three antifungal agents: ketoconazole (KCZ), terbinafine (TBF) and liranaftate (LNF).

Results: Biphasic peaks of scratching were observed at 1 h and at 6-7 h during an observation period of 14 h after trichophytin induction. For lesional skin, RNA was extracted 24 h after trichophytin challenge, and increased expression was seen in the genes for interleukin (IL)-17A, interferon-γ, tumour necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-2 and Dectin-1, whereas there was no obvious change in the genes for IL-31 and prostaglandin (PG)E2. Furthermore, KCZ inhibited histidine decarboxylase (HDC) expression in vitro and in vivo, and inhibited scratching in the very early phase. LNF inhibited expression of thymic stromal lymphopoietin (TSLP) and IL-8 in vitro, and TSLP, TNF-α, IL-1α and MIP2 in vivo, and also scratching in the early phase. TBF did not induce any significant alterations in either gene expression or scratching. DEX suppressed expression of all the chemical mediators except HDC in vitro and in vivo, and inhibited scratching.

Conclusion: Antifungals can inhibit itching induced by fungal infection through different mechanisms.

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology*
  • Chemokine CXCL2 / metabolism
  • Cytokines / drug effects
  • Cytokines / metabolism
  • Dermatitis, Contact / diagnosis
  • Dermatitis, Contact / drug therapy*
  • Dermatitis, Contact / etiology
  • Dermatitis, Contact / metabolism
  • Disease Models, Animal
  • Humans
  • Interferon-gamma / drug effects
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Keratinocytes / metabolism
  • Lectins, C-Type / drug effects
  • Lectins, C-Type / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR / metabolism
  • Mycoses / diagnosis
  • Mycoses / drug therapy
  • Mycoses / metabolism
  • Pruritus / immunology*
  • Pruritus / metabolism
  • Pruritus / physiopathology
  • Thymic Stromal Lymphopoietin
  • Tinea / diagnosis
  • Tinea / microbiology
  • Trichophytin / adverse effects*
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antifungal Agents
  • Chemokine CXCL2
  • Cytokines
  • Interleukin-17
  • Lectins, C-Type
  • Tumor Necrosis Factor-alpha
  • dectin 1
  • Trichophytin
  • Interferon-gamma
  • Thymic Stromal Lymphopoietin