br Preliminary remarks Expression of the transcription facto

Preliminary remarks Expression of the transcription factor aryl hydrocarbon receptor (AHR) and the AHR-repressor (AHRR) are both strikingly high in the AR-42 inhibitor australia of barrier organs skin and gut [1,2]. It is generally assumed that this reflects their role in linking environmental factors to an adapted cellular response. Indeed, old and new evidence demonstrate clearly that AHR-signaling (i) controls the induction of xenobiotic metabolizing enzymes (XME) where they are most needed, (ii) strengthens epithelial barrier capacity, and (iii) is involved in development and function of local immune cells. A plethora of molecules binds to AHR, causing down-stream gene induction. In this review we look at the skin. We review how man-made AHR ligands lead to skin toxicity, but also how AHR is involved in normal skin functions, and in situations of inflammation. The data so far is of staggering complexity, but a picture emerges where AHR-activity differs in inflammatory and healthy skin. This must be considered in preventive and therapeutic approaches targeted at interference with AHR-signaling.
AHR and skin toxicity Reports regarding skin toxicity of polycyclic aromatic hydrocarbons (PHAH) are much older than the discovery that they are potent AHR ligands [3,4]. By now it is established that the skin is an important xenobiotic metabolizing organ, which produces and induces cytochromes P450, epoxide hydroxylases and other enzymes [5]. In humans, exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a strong AHR activator and widespread environmental pollutant, can cause chloracne, hyperpigmentation, hyperkeratosis, and skin cancer, and exacerbate autoimmune disorders [6]. Chloracne is the cutaneous hallmark of acute accidental or occupational exposure to polychlorinated dibenzo-p-dioxins, dibenzofurans, dioxin-like polychlorinated biphenyls, and related polycyclic aromatic hydrocarbons (PAH) (e.g. in Yusho, Japan, 1968; Seveso, Italy, 1976; and Yucheng, Taiwan, 1979). Evidence points to a disturbance of sebocyte differentiation and lipid metabolism as the underlying mechanism [7]. In contrast to humans, mice and other laboratory animals do not develop chloracne-like diseases, albeit their keratinocytes are responsive to TCDD. The reasons for this – as for other species differences, especially TCDD lethality – are unknown. Species-specific differences might involve different AHR sequences shaping the ligand binding domain (possibly driven by evolution), different expression levels, or differences in the way AHR connects to other cellular signaling systems [8,9]. The flip-side to toxic effects of PAHs is the use of coal tar – a rich source of PHAHs and PAHs – as an efficient treatment in inflammatory skin diseases psoriasis and atopic dermatitis [10,11]. Here, AHR ligands in the coal tar are beneficial. This points to a big gap in the knowledge of AHR biology discussed also in other papers of this Current Opinion in Toxicology issue: how the beneficial versus adverse/toxic outcome of AHR activation is shaped by a complex web of parameters, including concurrent cellular events. In the skin this is particularly striking [12]. Therapeutic desiderata consider both agonist and antagonist treatment for many diseases (see Box 1).
Lack of AHR ligands mimics genetic AHR-deficiency One important observation that was made by several laboratories is that removal of ligands from the diet mimicked genetic AHR-deficiency, both in the gut and skin. Mice can be fed a synthetic diet free of flavonoids and glucosinolates, which contains a purified carbohydrate fraction and nutrients from non-plant sources. In mice fed this diet, the development of γδ T cells in the gut, type 3 innate lymphoid cells (ILC3) and lymphoid follicles follow the pattern observed in AHR-deficient mice [13,14]. In our lab we found that this AHR ligand-free diet impairs retention of water in the skin (a parameter of skin barrier integrity) of C57BL/6 mice similar to the skin barrier impairment in AHR-deficient mice. Interestingly, as was also found in the gut, re-addition of a single AHR-ligand precursor, indole-3-carbinol (I3C), to the diet rescued the adverse effect of a ligand-free diet (here: barrier integrity). Moreover, we demonstrated that feeding of this “spiked” diet for a limited time to young mice prevents later age-related skin barrier impairments [15]. Thus, presence or absence of AHR signaling in young animals can have consequences in aged animals. The underlying mechanisms are unclear, but epigenetic imprinting is a possibility. Epigenetic modifications even long-lasting ones have been shown upon AHR induction by TCDD, cigarette smoke, and various PAHs [16–20]. It is conceivable that similar epigenetic memory may occur with AHR-ligand containing diets; however, no data are available as yet. Thus, the observation of critical age windows may be another consideration in risk assessment as well as pharmacological/nutritional use of AHR ligands.