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.
Different bacteria-derived systems for regulatable gene expression have been developed for the use in mammalian cells and some were also successfully adopted for in vivo use in vertebrate model organisms. However, certain limitations apply to most of these systems, including leakiness of transgene expression, inefficient transgene silencing or activation, as well as limited tissue accessibility of transgene-inducers or their unfavourable pharmacokinetics. In this study, we evaluated the suitability of the lac-operon/lac-repressor (lacO/lacI) system for the regulation of the well-established Vav-gene promoter that allows inducible transgene expression in different haematopoietic lineages in mice. Using the fluorescence marker protein Venus as a reporter, we observed that the lacO/lacI system could be amended to modulate transgene-expression in haematopoietic cells. However, reporter expression was not uniform and the lacO elements introduced into the Vav-gene promoter only conferred limited repression and reversion of lacI-mediated gene silencing after administration of IPTG. Although further optimization of the system is required, the lacO-modified version of the Vav-gene promoter may be adopted as a tool where low basal gene-expression and limited transient induction of protein expression are desired, e.g. for the activation of oncogenes or transgenes that act in a dominant-negative manner.
Genetic deficiency or haploinsufficiency of the histidine-rich epidermal protein filaggrin (FLG) is associated with ichthyosis vulgaris (IV) and atopic dermatitis (AD). We investigated if the FLG genotype affects the microbiota composition of human skin and the cutaneous host response. FLG-deficient individuals had a low abundance of proteolytic Gram-positive anaerobic cocci (e.g. Finegoldia magna), which use peptides as nutrient sources. Furthermore, genes involved in histidine utilization were underrepresented in microbiota from FLG-deficient patients. An in vitro survival disadvantage of Finegoldia magna on FLGdeficient stratum corneum supported the in vivo findings. In co-cultures with primary human keratinocytes, Finegoldia magna induced a stronger antimicrobial peptide response than Staphylococcus aureus, whereas Staphylococcus aureus caused a stronger proinflammatory cytokine response than Finegoldia magna. Our data indicate that a common genetic defect can shape the cutaneous microbiome based on metabolic requirements of certain taxa, and may alter the host response to pathogens.
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