Science for Health
09 June 2014
The transcription factor aryl hydrocarbon receptor (AhR) is an evolutionarily conserved molecule that responds to environmental triggers. It has mainly been studied in the context of toxicology and its response to the environmental pollutant TCDD (dioxin). As such, AhR stimulation has been viewed as detrimental to the immune system. However, more recently the analysis of AhR-deficient mice has shown that AhR is important for the maintenance of barrier integrity in the gut via its effect on a range of intestinal immune cells.
The skin likewise is an important barrier organ and AhR is widely expressed in non-haematopoetic as well as haematopoietic cells present in the skin. Psoriasis, an inflammatory skin disease, is a chronic and immune-mediated disease characterised by highly-inflamed skin lesions resulting from immune cell infiltration, keratinocyte hyperproliferation and impaired differentiation. Both genetic and environmental factors are known to contribute to the disease, but the latter have not been investigated so far.
Paola Di Meglio and João Duarte, working in Gitta Stockinger’s lab in NIMR’s Division of Molecular Immunology, have shown that mice lacking AhR develop hyperinflammatory responses to a skin irritant that causes a psoriasis-like inflammation. In contrast, when wild-type mice were treated with a physiological AhR ligand that is generated by light-mediated degradation of tryptophan, the inflammatory symptoms were reduced.
Di Meglio and Duarte collaborated with dermatologists at King’s College, London and the University Hospital Kiel (Germany) as well as with Mike Gilchrist's lab at NIMR. They thereby showed that treatment of psoriasis patient biopsies with the AhR ligand down-regulated a substantial number of psoriasis-annotated genes, whereas treatment with an AhR antagonist caused their up-regulation even in non-lesional skin that does not yet show symptoms. The cells responsible for the exaggerated responses are keratinocytes, which release increased amounts of inflammatory chemokines and cytokines in the absence of AhR both in humans and in mice. Thus, the data show that physiological stimulation of AhR with a ligand that is rapidly degraded and therefore causes short-lived activation only, exerts a regulatory influence on inflammatory responses acting as an ‘inflammatory brake’.
Our findings indicate a previously unrecognised role for the AhR in keratinocytes exerting a regulatory influence on inflammatory immune responses. The difference between physiological AhR stimulation by, for example, tryptophan metabolites or dietary metabolites, to AhR stimulation by environmental toxins probably lies in the duration of signalling. Physiological ligands are rapidly degraded by AhR induced metabolic enzymes of the cytochrome P450 enzymes, whereas most pollutants are not good substrates for these enzymes and therefore cause prolonged AhR stimulation that interferes with important physiological AhR functions.
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Consequences of inflammatory signals and AhR activation (via light-induced generation of FICZ) on expression of inflammation related genes in keratinocytes. The image shows a section of skin with layers of keratinocytes (top layer stratum corneum).
Paola Di Meglio, João H. Duarte, Helena Ahlfors, Nick D.L. Owens, Ying Li, Federica Villanova, Isabella Tosi, Keiji Hirota, Frank O. Nestle, Ulrich Mrowietz, Michael J. Gilchrist, and Brigitta Stockinger (2014).
Activation of the Aryl Hydrocarbon Receptor Dampens the Severity of Inflammatory Skin Conditions
Immunity, epub ahead of print. Publishers full-text.
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