RESUMEN
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.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Microbioma Gastrointestinal/fisiología , Mediadores de Inflamación/metabolismo , Obesidad/metabolismo , Receptores de Hidrocarburo de Aril/fisiología , Animales , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/inmunología , Obesidad/inmunología , Transducción de Señal/fisiologíaRESUMEN
Accumulating evidence including studies of AHR-deficient mice and TCDD toxicity suggests multiple physiologic AHR functions. Challenges to identify responsible mechanisms are due to marked species differences and dependence upon cell type and cellular context. Transient AHR modulation is often necessary for physiologic functions whereas TCDD-mediated sustained receptor activation has been demonstrated to be responsible for toxic outcomes. To stimulate studies on responsible action mechanisms the commentary is focused on human AHR target genes and crosstalk with transcription factors. Discussed AHR functions include chemical and microbial defense, organ development, modulation of immunity and inflammation, reproduction, and NAD+-dependent energy metabolism. Obviously, much more work is needed to elucidate action mechanisms. In particular, studies of pathways leading to NAD+-dependent energy metabolism may shed light on the puzzling species differences of TCDD-mediated lethality and provide options for treatment of obesity and age-related degenerative diseases.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Receptores de Hidrocarburo de Aril/fisiología , Animales , Puntos de Control del Ciclo Celular/fisiología , Proliferación Celular/fisiología , Citocinas/metabolismo , Metabolismo Energético/fisiología , Humanos , Inactivación Metabólica/fisiología , Mastocitos/inmunología , Ratones , NAD/metabolismo , Dibenzodioxinas Policloradas/farmacocinética , Reproducción/fisiologíaRESUMEN
Diverse physiologic functions of AHR, a transcription factor discovered in studies of dioxin toxicity, are currently elucidated in many laboratories including chemical and microbial defense, immunity and myelopoiesis. Accumulating evidence suggests that AHR may also be involved in obesity and TCDD-mediated lethality in sensitive species. Underlying mechanisms include NAD+- and sirtuin-mediated deregulation of lipid, glucose and NAD+ homeostasis. Progress in NAD metabolome research suggests large consumption of NAD+ by NAD glycohydrolases (NADases) and NAD-dependent sirtuins. In focus are two NADases: (i) TiPARP (TCDD-induced poly(ADP-ribose) polymerase), one of several nuclear NADases, and (ii) plasma membrane-bound ectoNADase/CD38, a multifunctional enzyme and receptor. CD38 is involved in extra- and intracellular NAD degradation but acts also as differentiation marker. Both CD38 and AHR are components of a complex signalsome that enhances retinoic acid-induced differentiation of myeloid progenitor cells to granulocytes. Further advances of NAD metabolome research may lead to therapeutic options in the control of obesity and to improved risk assessment of TCDD toxicity.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Mielopoyesis/fisiología , NAD/metabolismo , Obesidad/metabolismo , Receptores de Hidrocarburo de Aril/fisiología , Animales , Diferenciación Celular/fisiología , Humanos , Obesidad/patología , Transducción de Señal/fisiologíaRESUMEN
Despite decades of intense research physiologic aryl hydrocarbon receptor (AHR) functions have not been elucidated. Challenges include marked species differences and dependence on cell type and cellular context. A previous commentary on human AHR functions in skin and intestine has been extended to vascular tissue. Similar functions appear to be operating in vascular tissue including microbial defense, modulation of stem/progenitor cells as well as control of immunity and inflammation. However, AHR functions are Janus faced: Detrimental AHR functions in vascular tissue are well documented, e.g., upon exposure to polycyclic aromatic hydrocarbons in cigarette smoke leading to oxidative stress and generation of oxidized LDL. Modified LDL particles accumulate in macrophages and smooth muscle-derived pro-inflammatory foam cells, the hallmark of atherosclerosis. On the other hand, numerous anti-inflammatory AHR agonists have been identified including bilirubin and quercetin. Mechanisms as to how AHR produces pro- and anti-inflammatory responses in the vascular system need further investigation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aterosclerosis/tratamiento farmacológico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/metabolismo , Aterosclerosis/metabolismo , Autoinmunidad , Bilirrubina/farmacología , Endotelio Vascular/metabolismo , Flavonoides/farmacología , Humanos , Lipoproteínas LDL/metabolismo , Hidrocarburos Policíclicos Aromáticos/toxicidad , Quercetina/farmacología , Transducción de SeñalRESUMEN
TCDD-mediated toxicity of human individuals together with animal studies led to identification of the aryl hydrocarbon receptor (AHR). It was characterized as multifunctional ligand-activated transcription factor and environmental sensor. Comparison of human toxic responses and animal models provide hints to physiologic AHR functions including chemical and microbial defense, homeostasis of stem/progenitor cells and modulation of the immune system in barrier organs such as skin and the gastrointestinal tract. Extrapolation from animals to humans is difficult due to marked species differences and dependence of AHR function on the cellular context. Nevertheless, therapeutic possibilities of AHR agonists and antagonists are in development. The AHR remains challenging and fascinating.