Depending on their chemical structure and properties, environmental chemicals and other xenobiotics that enter the cell can affect cellular function by either nonselective binding to cellular macromolecules or by interference with cellular receptors, which would initiate a more defined cell biological response. One of these intracellular chemosensor molecules is the aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family that is known to mediate the biochemical and toxic effects of dioxins, polyaromatic hydrocarbons and related compounds. Numerous investigations have revealed that the AhR is not only a master regulator of drug metabolism activated by anthropogenic chemicals, but is also triggered by natural and endogenous ligands and can influence cell biological endpoints such as growth and differentiation. Cutting-edge research has identified new intriguing functions of the AhR, such as during proteasomal degradation of steroid hormone receptors, the cellular UVB stress response and the differentiation of certain T-cell subsets. In this review we provide both a survey of the fundamental basics of AhR biology and an insight into new functional aspects of AhR signaling to further stimulate research on this intriguing transcription factor at the interface between toxicology, cell biology and immunology.
Among other functions, the skin serves as the barrier against the environment and provides vital protection from physical or chemical harm and from infection. Skin cells express the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and sensor of environmental chemicals; at the same time, AHR ligands are abundant in skin from exogenous or endogenous sources. For example, solar radiation, in particular ultraviolet (UV) B, generates AHR ligands from tryptophan in the skin. Recent evidence has shown that AHR is involved in the (patho)physiology of skin including the regulation of skin pigmentation, photocarcinogenesis, and skin inflammation. We here provide a state-of-the-art summary of work which relates to the role of the AHR in (1) adaptive responses against environmental challenges such as UVB or topical chemicals and (2) intrinsic developmental roles for homeostasis of skin cells and (3) skin immunity. We also discuss the existing evidence that AHR antagonists or AHR ligands may be used for the prevention and/or treatment of skin disease.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor expressed in all skin cell types, which is critically involved in the pathogenesis of a variety of skin diseases and thus represents a potential therapeutic target. Recent studies indicate that blocking AHR activation is desirable in some skin conditions, whereas the opposite, i.e., stimulation of AHR activation, is beneficial in another group of skin disorders. We here propose a model based on qualitative differences in canonical versus non-canonical AHR signaling to reconcile these seemingly contradictory observations.
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