Microarray analysis of the AHR system: Tissue-specific flexibility in signal and target genes

Self Cite

127

115

Langerhans cells (LC) are professional APCs of the epidermis. Recently, it was suggested that they are tolerogenic and control adverse immune reactions, including against low molecular mass chemicals. The aryl hydrocarbon receptor (AhR), a ligandactivated transcription factor, is involved in low molecular mass chemical metabolism and cell differentiation. Growing evidence suggests a role for the AhR in the immune system, for example, by influencing dendritic cell and T cell differentiation. We found that the AhR and its repressor AhRR are expressed in LC of C57BL/6 mice. LC, unexpectedly, did not respond to a strong AhR agonist with induction of transcripts of xenobiotic metabolizing enzymes. To test for a physiological role of the AhR in LC, we investigated how AhR deficiency affects LC. We found that AhR-deficient LC were impaired in maturation; they remained smaller and less granular, did not up-regulate expression of costimulatory molecules CD40, CD80, and CD24a during in vitro maturation, and their phagocytic capacity was higher. Interestingly, the mRNA expression of tolerogenic Ido was severely decreased in AhR-deficient LC, and enzyme activity could not be induced in AhR-deficient bone marrow-derived dendritic cells. GM-CSF, needed for LC maturation, was secreted in significantly lower amounts by AhR-deficient epidermal cells. Congruent with this impaired maturity and capacity to mature, mice mounted significantly weaker contact hypersensitivity against FITC. Our data suggest that the AhR is involved in LC maturation, both cell autonomously and through bystander cells. At the same time, the AhR might be part of the risk strategy of LC against unwanted immune activation by potential skin allergens.

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice

Jux

Kadow

Esser

2009

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127

115

“…AhR functional expression has been reported in NK T cells, TCRgd T cells, macrophages, and dendritic cells, all located at the interface between innate and acquired immune system (25,29,30), suggesting that environmental factors as well as metabolic products have a role in the development of local cells and immune response. In this study, to our knowledge we show for the first time that murine and human MCs constitutively express AhR, whose activation by FICZ is able to influence both FcεRI-mediated early degranulation response and FcεRI-independent IL-6 and IL-17 cytokine production.…”

Section: Discussionmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Sibilano

Frossi

Calvaruso

et al. 2012

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.

“…Recently, it was discovered that AhR interacts also with other signaling molecules, such as NF-kB, estrogen receptor, or STAT1 (27)(28)(29). As a consequence, AhRmediated gene induction is highly context dependent and cell specific (30,31). The intracellular abundance of AhR differs markedly between cells, even if they are closely lineage related, such as peripheral CCR6 + and CCR6 2 gd T cells (32).…”

mentioning

confidence: 99%

Aryl Hydrocarbon Receptor Is Critical for Homeostasis of Invariant γδ T Cells in the Murine Epidermis

Kadow

Jux

Zahner

et al. 2011

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133

123

An immunoregulatory role of aryl hydrocarbon receptor (AhR) has been shown in conventional αβ and γδ T cells, but its function in skin γδ T cells (dendritic epidermal T cells [DETC]) is unknown. In this study, we demonstrate that DETC express AhR in wild-type mice, and are specifically absent in the epidermis of AhR-deficient mice (AhR-KO). We show that DETC precursors are generated in the thymus and home to the skin. Proliferation of DETC in the skin was impaired in AhR-KO mice, resulting in a >90% loss compared with wild type. Surprisingly, DETC were not replaced by αβ T cells or conventional γδ T cells, suggesting a limited time frame for seeding this niche. We found that DETC from AhR-KO mice failed to express the receptor tyrosine kinase c-Kit, a known growth factor for γδ T cells in the gut. Moreover, we found that c-kit is a direct target of AhR, and propose that AhR-dependent c-Kit expression is potentially involved in DETC homeostasis. DETC are a major source of GM-CSF in the skin. Recently, we had shown that impaired Langerhans cell maturation in AhR-KO is related to low GM-CSF levels. Our findings suggest that the DETCs are necessary for LC maturation, and provide insights into a novel role for AhR in the maintenance of skin-specific γδ T cells, and its consequences for the skin immune network.