Towards Targeting the Aryl Hydrocarbon Receptor in Cystic Fibrosis.

Tryptophan (trp) metabolism is an important regulatory component of gut mucosal homeostasis and the microbiome. Metabolic pathways targeting the trp can lead to a myriad of metabolites, of both host and microbial origins, some of which act as endogenous low-affinity ligands for the aryl hydrocarbon receptor (AhR), a cytosolic, ligand-operated transcription factor that is involved in many biological processes, including development, cellular differentiation and proliferation, xenobiotic metabolism, and the immune response. Low-level activation of AhR by endogenous ligands is beneficial in the maintenance of immune health and intestinal homeostasis. We have defined a functional node whereby certain bacteria species contribute to host/microbial symbiosis and mucosal homeostasis. A microbial trp metabolic pathway leading to the production of indole-3-aldehyde (3-IAld) by lactobacilli provided epithelial protection while inducing antifungal resistance via the AhR/IL-22 axis. In this review, we highlight the role of AhR in inflammatory lung diseases and discuss the possible therapeutic use of AhR ligands in cystic fibrosis.

Learning from other diseases: protection and pathology in chronic fungal infections.

Fungal commensals coexist in a complex milieu of bacteria within the human body. An increased understanding of the importance of microbiota in shaping the host's immune and metabolic activities has rendered fungal interactions with their hosts more complex than previously appreciated. Metagenomics has revealed the complex interactions between fungal and bacterial commensals that, either directly or through the participation of the host immune system, impact on immune homeostasis at mucosal surfaces that, in turn, lead to secondary fungal infections. Metabolomics has captured the dialogue between the mammalian host and its microbiota. It appears that the host tryptophan catabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) plays a dominant role in the interplay between tryptophan catabolism by microbial communities, the host's own pathway of metabolite production, and the activation of the aryl hydrocarbon receptor (AhR)/IL-22 axis, eventually impacting on mucosal immune homeostasis and host/fungal symbiosis. Thus, the regulatory loop involving AhR and IDO1 may be exploited for the development of multi-pronged host- and microbiota-directed therapeutic approaches for mucosal and systemic fungal diseases.

Antioxidant systems and lymphocyte proliferation in the horse, sheep and dog.

To better define the species-specific antioxidant systems and to ascertain the influence of the intracellular redox status on the immune system of different animal species, we determined lymphocyte glutathione peroxidase (GSHPx) activity, plasmatic glutathione levels (GSH) and the effect of H2O2 on the responsiveness of lymphocytes to proliferative stimuli. Among the three species considered, sheep presented the lowest plasmatic GSH and the highest lymphocyte GSHPx activity. On the contrary, dogs showed an inverted pattern (high GSH - low GSHPx). Horses displayed intermediate values for both parameters analysed. The effect of H2O2 on the proliferative capacity of lymphocytes was the same for all three species; the 200 microM dose in particular was strongly inhibiting. Each species, however, showed different rates of inhibition: sheep exhibited the highest sensitivity to the antiproliferative effect of H2O2. Our results confirmed that high H2O2 concentrations (200 microM) are noxious for the cellular functions of all animals; however this effect is mediated by a rigorously species-specific relationship between the intracellular reactive oxygen species (ROS) and the molecular systems involved in cell proliferation.