Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

Matthias Schäfer,Jean‐Hilaire Saurat,Hans‐Dietmar Beer,Svitlana Kurinna,Marlon R Schneider,Lutz Langbein,Sabine Werner,Ann‐Helen Willrodt,Florian Gruber,Aaron J Huebner,Dennis R Roop,Alexandra Geusau,Andrea S Link,Olivier Sorg,Erwin Tschachler,Konrad Sandhoff,Hany Farwanah,Wilhelm Bloch

doi:10.1002/emmm.201303281

Abstract

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin-induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.

Highlights

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention
Histological analyses and immunofluorescence staining for perilipin 2 showed that the sebaceous glands (SG) in back and tail skin (Fig 1A,B) and the meibomian glands of the eyelids (Supplementary Fig 1A) are strongly enlarged in K5cre-CMVcaNrf2 mice
The pathology of metabolizing acquired dioxin-induced skin hamartomas (MADISH) patients develops after intoxication with halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Summary

Introduction

The transcription factor Nrf is a key regulator of the cellular stress response, and pharmacological Nrf activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf target This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/metabolizing acquired dioxin-induced skin hamartomas (MADISH) patients. These results identify novel Nrf activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis

Methods

Results

Conclusion