More than a cell biosensor: aryl hydrocarbon receptor at the intersection of physiology and inflammation

Aryl hydrocarbon receptor (AhR), a highly conserved intracellular transcription factor, is activated by a plethora of ligands of both exogenous and endogenous nature. Besides activating xenobiotic-metabolizing enzymes, it is involved in the differentiation and development of hematopoietic, hepatic, nervous and immune systems. More and more data describe its role in the regulation of immune responses and in the onset and progression of inflammation. Particularly, established results view AhR as a downstream target of inflammatory molecules, since its transcription is regulated by the inflammatory cascade. Interleukin 6 (IL-6) has been described to sustain early stages of inflammation and to influence the expression of AhR either directly, following signal transducer and activator of transcription 3 (STAT3) activation, or in combination with other inflammatory mediators, e.g., transforming growth factor-β (TGF-β). In selected inflammatory milieus, once activated, AhR interacts with its targets including the IL-6 promoter, thus originating an autoinflammatory loop. This perspective review brings together evidence that, in some IL-6-driven pathways, AhR is a downstream target that amplifies the duration and extent of inflammation. Considering that many inflammatory mediators can also trigger the activities of AhR as biosensor and activator of xenobiotics metabolism, this issue is of pivotal importance. The individual susceptibly to some environmental ligands of AhR can be probably explained by considering the individual inflammatory state, which could additionally fuel the proinflammatory activity of AhR. Thus, AhR could be considered a transductor of a dynamic, bidirectional connection between internal and external environmental stimuli and the inflammatory response.