How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function

Abstract

Increasingly, the aryl hydrocarbon receptor (AHR) is being recognized as a sensor for endogenous and pseudo-endogenous metabolites, and in particular microbiota and host generated tryptophan metabolites. One proposed explanation for this is the role of the AHR in innate immune signaling within barrier tissues in response to the presence of microorganisms. A number of cytokine/chemokine genes exhibit a combinatorial increase in transcription upon toll-like receptors and AHR activation, supporting this concept. The AHR also plays a role in the enhanced differentiation of intestinal and dermal epithelium leading to improved barrier function. Importantly, from an evolutionary perspective many of these tryptophan metabolites exhibit greater activation potential for the human AHR when compared to the rodent AHR. These observations underscore the importance of the AHR in barrier tissues and may lead to pharmacologic therapeutic intervention.

The aryl hydrocarbon receptor in liver inflammation

“…Of note, knowledge about the kinetics of AHR ligand activity is an important prerequisite for therapeutic application. On the one hand, sufficient bioavailability is important for effectiveness; on the other hand, persistence of AHR ligand binding might have adverse effects [76]. Moreover, there is accumulating evidence that many AHR ligands exert their functions in an organ-or cell-specific manner [76][77][78] Table 2, offering the opportunity for the selection of specific AHR ligands or the design of tailor-made synthetic AHR agonists or antagonists according to the respective therapeutic indication [77,78].…”

“…On the one hand, sufficient bioavailability is important for effectiveness; on the other hand, persistence of AHR ligand binding might have adverse effects [76]. Moreover, there is accumulating evidence that many AHR ligands exert their functions in an organ-or cell-specific manner [76][77][78] Table 2, offering the opportunity for the selection of specific AHR ligands or the design of tailor-made synthetic AHR agonists or antagonists according to the respective therapeutic indication [77,78]. However, a major caveat for the pharmaceutical use of such selective AHR modulators remains the limited predictability of their in vivo function, requiring extensive testing in order to prevent unwanted side effects [77,78].…”

The Aryl Hydrocarbon Receptor in Energy Balance: The Road from Dioxin-Induced Wasting Syndrome to Combating Obesity with Ahr Ligands

“…For example, several laboratories are now identifying how the AHR, the gut microbiota, and the tryptophan metabolites they produce can be targeted to influence not only metabolic disease states [112][113][114][115], but neoplastic diseases as well [116,117]. For a more comprehensive review on the interaction of the AHR and the gut microflora, we refer the reader to another manuscript in this Special Issue of the International Journal of Molecular Sciences, entitled "How Ah Receptor Ligand Specificity Became Important in Understanding its Physiological Function" [118].…”

The aryl hydrocarbon receptor at the forefront of host‐microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications

“…Importantly, many natural and physiological AHR ligands and their sources were identified over the years (reviewed by Murray and Perdew 5 ). Key physiological events are mediated or co‐regulated by AHR signalling, which in the in skin encompass cellular proliferation, 6 differentiation, 7 , 8 , 9 maturation 10 , 11 and migration.…”