Epidermal Overexpression of Xenobiotic Receptor PXR Impairs the Epidermal Barrier and Triggers Th2 Immune Response

Abstract

The skin is in daily contact with environmental pollutants, but the long-term effects of such exposure remain underinvestigated. Many of these toxins bind and activate the pregnane X receptor (PXR), a ligand-activated transcription factor that regulates genes central to xenobiotic metabolism. The objective of this work was to investigate the effect of constitutive activation of PXR in the basal layer of the skin to mimic repeated skin exposure to noxious molecules. We designed a transgenic mouse model that overexpresses the human PXR gene linked to the herpes simplex VP16 domain under the control of the keratin 14 promoter. We show that transgenic mice display increased transepidermal water loss and elevated skin pH, abnormal stratum corneum lipids, focal epidermal hyperplasia, activated keratinocytes expressing more thymic stromal lymphopoietin, a T helper type 2/T helper type 17 skin immune response, and increased serum IgE. Furthermore, the cutaneous barrier dysfunction precedes development of the T helper type 2/T helper type 17 inflammation in transgenic mice, thereby mirroring the time course of atopic dermatitis development in humans. Moreover, further experiments suggest increased PXR signaling in the skin of patients with atopic dermatitis when compared with healthy skin. Thus, PXR activation by environmental pollutants may compromise epidermal barrier function and favor an immune response resembling atopic dermatitis.

Filaggrin null mutations are associated with altered circulating Tregs in atopic dermatitis

“…Tregs exposed to phenanthrene show decreased TGF‐β and IL‐10 and increased IL‐4, IL‐13, (p)STAT6 and GATA‐3 . It has recently been shown that repeated exposure to air pollution and to noxious molecules may promote AD . Thus, pollutants may contribute to AD also via their ability to affect Treg populations, especially by impeding their immunosuppressive capacity by causing them to redifferentiate into Th‐like cells that produce proinflammatory cytokines.…”

“…Worldwide, AD prevalence is relatively high, affecting 15%‐30% of children and 2%‐10% of adults. Notably, AD prevalence has markedly increased during the past 40 years, potentially because of a higher pollution burden …”

“…Notably, AD prevalence has markedly increased during the past 40 years, potentially because of a higher pollution burden. [1][2][3][4] The pathogenesis of AD is complex and not yet fully understood.…”

“…Notably, AD prevalence has markedly increased during the past 40 years, potentially because of a higher pollution burden. [1][2][3][4] The pathogenesis of AD is complex and not yet fully understood.Epidermal barrier defects and immune hyper-responsiveness are the main features of AD. Meta-analysis of genome-wide association studies identified a risk locus in the epidermal differentiation complex and especially the filaggrin (FLG) gene.…”

Progress in Understanding Atopic Dermatitis

“…A major advance came with the genetic demonstration that significant numbers of AD patients had FLG deficiency that compromises the epidermal barrier, allowing penetration of bacteria, allergens, and environmental chemicals and pollutants. Increases of these xenobiotics in urban regions combined with barrier access has been shown to act on keratinocytes to trigger the transcription factor PXR (Elentner et al, 2018) and the aryl hydrocarbon receptor, both of which can work to cause AD worsening and even downstream release of TSLP and activation of the T helper (Th) type 2 pathway (Hidaka et al, 2017).…”