Nrf br AhR br Nrf and AhR friends or foes

Nrf2
AhR
Nrf2 and AhR: friends or foes for energetic metabolism?
Perspectives in carcinogenesis upon xenobiotic exposure
Acknowledgements
Introduction Integration of endogenous and exogenous signals via appropriate receptors is at the core of biological differentiation and adaptive responses to the environment. The transcription factor aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor [1,2], well known for its role in inducing genes coding for xenobiotic metabolizing enzymes. Ligands comprise a broad and astonishingly diverse range of small molecular weight chemicals, among them anthropogenic environmental pollutants, but also natural plant compounds considered healthy [3,4]. The names “aryl hydrocarbon receptor” and “dioxin receptor” reflect the historical fact that the first ligands used to identify and study AHR were polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs), in particular 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic chemical. TCDD is immunosuppressive at low doses, and this discovery sparked early the interest in AHR by immunotoxicologists. As detailed below, AHR-mediated gene fludarabine synthesis changes are involved in cell differentiation of many immune cells, their proliferation, inflammatory and regulatory immune responses, barrier immunity and bacterial defense [5–8]. Relevant AHR-ligands for these physiological responses are endogenously generated or diet-derived ligands, in particular tryptophan metabolites, indoles, or polyphenols. Currently, new “AHR-topics” emerge at a breath-taking speed, and as a consequence literature is expanding tremendously. We here review toxic and beneficial effects of AHR on the immune system and in particular look at two areas with future importance. Finally, we consider the parameters, which must be integrated to predict beneficial versus adverse effects of ligands and AHR signaling on the immune system.
AHR plays a role for adverse and beneficial immune responses
What influences adverse versus beneficial outcome of AHR-signaling? From the data presented above, it is clear that AHR-activation is critical for many immune responses, but can also impair immunity and cause, e.g., unwanted immunosuppression. As the issue is important and researched intensely, we want to end this review by pointing out the major factors influencing the outcome of AHR signals by differing ligands (see Box 1). While dose is very important, perhaps even the most important parameter, it is not the only parameter. Of particular importance are also the affinity to AHR and half-life of the ligand in question, as mentioned above [42]. Xenobiotic metabolizing enzymes can quickly remove a ligand from cells. In fact, experimental excessive Cyp1a1 expression in mice led to depletion of gut AHR-ligands, resulting in a quasi AHR-deficient state [77]. Some ligands have additional non-AHR-specific effects; they may be, for instance, anti-oxidants as well. Tissue-specific AHR expression levels are conceivably relevant for effects, as exemplified by the high AHR expression identified in Th17 cells, but not in other T helper cells [18]. Polymorphisms must be considered as well. For the mouse and rats high-affinity and poor-affinity Ahr variants are known [29]. In humans, particular functional SNPs, such as rs2066853, were identified, which render persons more susceptible for certain risks (see above). Finally, there is still much to learn about the cellular and gene-site context: the influence of number and spacing of XREs [83,84] or of additional promoter elements, which modulate the transcriptional outcome upon AHR-ligand binding at XRE sites [78–81]. Importantly, AHR-activity might be different in inflamed or otherwise active tissues than in healthy tissues, as AHR can bind to and interact with, e.g., NFκB components [82], STAT (signal transducer and activator of transcription) molecules [83,84] and more.