The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health

Abstract

Much of what is known about the Aryl Hydrocarbon Receptor (AhR) centers on its ability to mediate the deleterious effects of the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). However, the AhR is both ubiquitously-expressed and evolutionarily-conserved, suggesting that it evolved for purposes beyond strictly mediating responses to man-made environmental toxicants. There is growing evidence that the AhR is required for the maintenance of health, as it is implicated in physiological processes such as xenobiotic metabolism, organ development and immunity. Dysregulation of AhR expression and activity is also associated with a variety of disease states, particularly those at barrier organs such as the skin, gut and lungs. The lungs are particularly vulnerable to inhaled toxicants such as cigarette smoke. However, the role of the AhR in diseases such as chronic obstructive pulmonary disease (COPD)-a respiratory illness caused predominately by cigarette smoking-and lung cancer remains largely unexplored. This review will discuss the growing body of literature that provides evidence that the AhR protects the lungs against the damaging effects of cigarette smoke.

Keywords: aryl hydrocarbon receptor; chronic obstructive pulmonary disease; cigarette smoke; lung.

Figure 1

Diagrammatic representation of Aryl hydrocarbon receptor (AhR) signaling pathways. Canonical AhR Signaling (solid black arrows)-Inactivated AhR is found in the cytosol (solid circle) complexed to a HSP90 homodimer, XAP2 and p23. (1) Ligand binding to the AhR induces the (2) translocation of the AhR complex from the cytoplasm to the nucleus (dashed circle). In the nucleus the AhR dissociates from its chaperone proteins, (3) heterodimerizes with ARNT and binds to DRE sequences to induce transcription of target genes. Non-canonical AhR Signaling (dashed purple arrows)-The AhR can heterodimerize with a variety of proteins to mediate diverse downstream effects. (4) When complexed with the estrogen receptor (ER), the AhR functions as an E3-ligase to mediate ER ubiquitination and degradation. (5) The AhR also mediates phosphorylation events, such as the phosphorylation of Akt and ERK proteins in the cytoplasm. (6) The AhR can also bind to the NFκB family members RelA and RelB, where it can regulate the expression of pro-inflammatory mediators such as IL6, COX-2 and ICAM1. (7) The AhR can also regulate the subcellular localization of RNA-binding proteins such as HuR, thereby indirectly influencing mRNA stability and thus expression of pro-inflammatory mediators such as COX-2.

Figure 2

The AhR exerts protective effects in the lungs by attenuating CS-induced lung injury. The AhR attenuates an inter-connected web of pathogenic mechanisms that have been independently established to contribute to the progression of COPD. More specifically, the AhR may contribute to the attenuation of CS-induced inflammation via its role in (1) suppressing CS-induced pulmonary neutrophilia. Additionally, the AhR may attenuate CS-induced oxidative stress via its role in (2) suppressing CS-induced ROS production and (3) promoting the upregulation of anti-oxidants in response to CS. The AhR may also protect against CS-induced lung parenchymal destruction through its ability to (4) reduce the loss of lung structural cells by promoting cellular proliferation and attenuating CS-induced apoptosis and cellular senescence. (5) Finally, the AhR may protect the lungs against bacterial infections that could otherwise trigger COPD-associated exacerbations, such as S. Pneumoniae and P. aeruginosa, by promoting neutrophil infiltration. Black arrows represent promotion and red bars represent inhibition.