WG Esser: Role of AhR in immuntoxicology

Projects

1. Role of AHR for the gut microbiome

Unbalancing the immune system is a hallmark of dioxin activity and of other persistent polycyclic aromatic hydrocarbons, many of which are still abundant in the environment. Surprisingly, data on the effect of dioxins on the gut microbiome are still sparse, despite the fact that the oral route is the major route of uptake for these chemical pollutants. Recent research has demonstrated that the AHR is critical for a functioning gut immune system and keeping pathogenic gut bacteria in check. Indeed, lack of plant-derived AHR-ligands in the diet leads to higher susceptibility towards infections and can impair the gut barrier. Our research aims to unravel whether and how dioxin changes the gut microbiome and what might be the consequences for the immune system. We will also analyse this in the context of a “wester diet”, i.e. a highly caloric and rich in fat diet. In addition, we establish an easy and accessible tool for profiling the gut microbiota community by flow cytometry. This can then be used for many studies, such as the impact of microplastic or cadmium on the gut microbiota. (grant DFG ES103/9-1)

2. Barrier function of the skin and skin immune cells

The skin and especially the epidermis are in constant contact with the „outer world“ and are immunologically active. Disruption of the barrier function of the skin can have serious health consequences. Skin hosts its own microbiota – a community of commensal bacteria, which also wards off pathogenic bacteria. Diseases such as psoriasis or atopic dermatitis are associated with breaks of the skin barrier and with typical changes to the skin microbiota with pathogenic bacteria. We had shown that the AHR is highly expressed in all skin cells, and controls cell-specific functions. Indeed, genetic deficiency of AHR or deletion of AHR ligands from the diet impaired the skin barrier. The latter could be rescued again by addition of AHR ligands to the diet, which improved skin barrier measurements such as transepidermal water loss. We are interested in analyzing the gut-skin axis further and address how the gut microbiota and their metabolites influence skin health. This project is integrated with another project 3, where we look at epidermal γδ T cells as players in skin immunity and health.

3. Epidermal γδ T cells

Skin harbors a special subset of T cells, which have features of innate and adaptive immune cells. These γδ T cells bear a receptor of unknown antigen specificity, are generated exclusively during a short time-window in the fetal thymus and play an important role in immunosurveillance of the skin, i.e. fighting viral and bacterial pathogens, eliminating cancer cells, and supporting wound healing.

We found that the skin of AHR-deficient mice is almost completely devoid of these cells, although they are formed in the fetal thymus and reach the skin around birth. However, they disappear within a few weeks. With gene expression profiles, we made the original finding that inflammatory pathways are upregulated in AHR-deficient γδ T cells, an indication that a role of AHR exists in dampening an inflammatory default of these cells. We want to study this further in the future and add the aspect of energy metabolism. This builds on our discovery that addition of the small chain fatty acid butyrate, an important energy source for T cells, to γδ T cell cultures results in lower secretion of the inflammatory cytokine IFNγ.

Non-melanoma skin cancer is one of the most common tumors world-wide, with rising frequency. However, the role of local immune cells in the skin to recognize and fight this cancer is not understood very well. Therefore, we will develop relevant human 3-D skin models with integrated γδ T cells. With such models, we want to query the potency of γδ T cells in recognizing and killing skin tumor cells. Furthermore, we ask whether the AHR, a sensor for UV irradiation and UV-stress in the skin, has a role in immunosurveillance. This project is funded by the Wilhelm-Sander Foundation (www.sanst.de).