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Allergen-induced dermatitis causes alterations in cutaneous retinoid-mediated signaling in mice.

ABSTRACT: Nuclear receptor-mediated signaling via RARs and PPAR? is involved in the regulation of skin homeostasis. Moreover, activation of both RAR and PPAR? was shown to alter skin inflammation. Endogenous all-trans retinoic acid (ATRA) can activate both receptors depending on specific transport proteins: Fabp5 initiates PPAR? signaling whereas Crabp2 promotes RAR signaling. Repetitive topical applications of ovalbumin (OVA) in combination with intraperitoneal injections of OVA or only intraperitoneal OVA applications were used to induce allergic dermatitis. In our mouse model, expression of IL-4, and Hbegf increased whereas expression of involucrin, Abca12 and Spink5 decreased in inflamed skin, demonstrating altered immune response and epidermal barrier homeostasis. Comprehensive gene expression analysis showed alterations of the cutaneous retinoid metabolism and retinoid-mediated signaling in allergic skin immune response. Notably, ATRA synthesis was increased as indicated by the elevated expression of retinaldehyde dehydrogenases and increased levels of ATRA. Consequently, the expression pattern of genes downstream to RAR was altered. Furthermore, the increased ratio of Fabp5 vs. Crabp2 may indicate an up-regulation of the PPAR? pathway in allergen-induced dermatitis in addition to the altered RAR signaling. Thus, our findings suggest that ATRA levels, RAR-mediated signaling and signaling involved in PPAR? pathways are mainly increased in allergen-induced dermatitis and may contribute to the development and/or maintenance of allergic skin diseases.

SUBMITTER: Gericke J

PROVIDER: S-EPMC3744553 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Allergen-induced dermatitis causes alterations in cutaneous retinoid-mediated signaling in mice.

Gericke Janine J Ittensohn Jan J Mihály Johanna J Dubrac Sandrine S Rühl Ralph R

PloS one 20130815 8

Nuclear receptor-mediated signaling via RARs and PPARδ is involved in the regulation of skin homeostasis. Moreover, activation of both RAR and PPARδ was shown to alter skin inflammation. Endogenous all-trans retinoic acid (ATRA) can activate both receptors depending on specific transport proteins: Fabp5 initiates PPARδ signaling whereas Crabp2 promotes RAR signaling. Repetitive topical applications of ovalbumin (OVA) in combination with intraperitoneal injections of OVA or only intraperitoneal O ...[more]

PMID: 23977003

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Project description:IntroductionRecent evidence has demonstrated that the microbiome is a driver of the underlying pathophysiological mechanisms of respiratory disease. Studies have indicated that bacterial metabolites produced in the gut and lung can impact lung inflammation and immune cell activity, affecting disease pathology. Despite asthma being a disease with marked sex differences, experimental work linking microbiomes and asthma has not considered the sex variable.MethodsTo test the hypothesis that the lung and gut microbial composition impacts allergic lung inflammation in a sex-specific manner, we evaluated lung and gut microbiome alterations in a mouse model of allergic inflammation and assessed their association with lung function and inflammation phenotypes. For this, we exposed male and female adult C57BL/6J mice intranasally to 25 µg of a house dust mite extract mix (HDM) daily, or phosphate-buffered saline (PBS) as control, for 5 weeks (n = 4-6/group). DNA from fecal pellets collected before and after the 5-week treatment, and from lung tissue collected at endpoint, was extracted using the ZymoBIOMICS®-96 MagBead DNA Kit and analyzed to determine the 16S microbiome via Targeted Metagenomic Sequencing.ResultsThe HDM treatment induced a sex-specific allergic inflammation phenotype with significantly higher neutrophilia, lymphocytosis, inflammatory gene expression, and histopathological changes in females than males following exposure to HDM, but higher airway hyperresponsiveness (AHR) in males than females. In addition, sex-specific lung gene expression and associated pathways were identified HDM mix after challenge. These changes corresponded to sex-specific alterations in the gut microbiome, where the Firmicutes to Bacteroidetes ratio (F:B) was significantly reduced in fecal samples from only male mice after HDM challenge, and alpha diversity was increased in males, but decreased in females, after 5-weeks of HDM treatment.DiscussionOverall, our findings indicate that intranasal allergen challenge triggers sex-specific changes in both gut and lung microbiomes, and induces sex-specific lung inflammation, AHR, and lung inflammatory gene expression pathways, suggesting a contribution of the lung-gut axis in allergic airway disease.

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Allergen-induced dermatitis causes alterations in cutaneous retinoid-mediated signaling in mice.

Publications

Allergen-induced dermatitis causes alterations in cutaneous retinoid-mediated signaling in mice.

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