Aryl hydrocarbon receptor (AHR) functions: Balancing opposing processes including inflammatory reactions

Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of physiologic AHR functions. Control of AHR functions is challenged by the fact that AHR is often involved in balancing opposing processes. Two AHR functions are discussed. (i) Microbial defense: intestinal microbiota commensals secrete AHR ligands that are important for maintaining epithelial integrity and generation of anti-inflammatory IL-22 by multiple immune cells. On the other hand, in case of microbial defense, AHR-regulated neutrophils and Th17 cells are involved in generation of bactericidal reactive oxygen species and pro-inflammatory stimuli. However, during the process of infection resolution, 'disease tolerance' is achieved. (ii) Energy, NAD⁺ and lipid metabolism: In obese individuals AHR is involved in either generation or inhibition of fatty liver and associated hepatitis. Inhibition of hepatitis is mainly achieved by regulating NAD⁺-controlled SIRT1, 3 and 6 activity. Interestingly, these enzymes are synergistically modulated by CD38, an NAD-consuming NAD-glycohydrolase. It is proposed that inflammatory responses may be beneficially modulated by AHR agonistic and CD38 inhibiting phytochemicals. Caveats in presence of carcinogenicity have to be taken into account. AHR research is an exciting field but therapeutic options remain challenging.