Esser research group: role of AhR in immuntoxicology
The Esser lab studies the role of the aryl hydrocarbon receptor (AhR) in immunotoxicology, in particular in differentiation, function and mobility of lymphoid cells in the barrier organs skin and gut. AhR is a transcription factor, which senses certain small molecular weight chemicals in the environment and thereby mediates an adaptive response of cells to such signals. For instance, cells can respond to chemicals with upregulation of relevant metabolizing enzymes. In addition, many immune (and other) cells use AhR signaling in normal differentiation. The Esser lab showed for the first time in mice that AhR is necessary for the maturation and function of two distinct immune cell types of the skin, the Langerhans cells and dendritic epidermal T cells. Also AhR was shown to influence oral tolerance, an important immunological feature of the gut, which ensures that food proteins are ignored by the immune system. Building on these results, the lab focusses currently on (i) the role of AhR for skin barrier functions and skin T cells, and (ii) immunostimulation versus immunosuppression by AhR. Depending on the organ studied, either UV (which generates a high-affinity AhR ligand in the skin), or AhR activating food constituents such as indole-3-carbinol are used. A number of mouse models were developed which are used, also in cooperation with the labs of Haarmann-Stemmann and Krutmann at the IUF, to study immunological functions and the preventive and therapeutic potential of AhR in depth.
1. Barrier functions of the skin
The skin, in particular the epidermis, is the outermost barrier to the environment, with which it interacts. Epidermis is also active as an immune organ. Disruptions of skin barrier functions can have serious health consequences. The skin is populated by a plethora of microorganisms, which together are called the “microbiom”, and increasing evidence suggests that the microbiom is beneficial for health. For instance, diseases such as psoriasis or atopic dermatitis are associated with changes in the microbiom, and shifts towards more pathogenic skin bacteria. Research at the IUF has demonstrated that AhR is expressed highly in most skin cells. Lack of AhR has consequences for skin immune cell functions, and leads to decrease in the frequency of certain skin immune cells, which contribute to barrier integrity. Obviously, this can be relevant for skin barrier and the microbiom, but little is known. In our project on the role of AhR for skin barrier function we address this gap, and study the skin barrier and skin microbiom in situations of AhR-deficiency. Ultimately, we want to define therapeutic opportunities in strengthening skin barrier. This project is done in close collaboration with the Haarmann-Stemmann and Krutmann labs.
2. Epidermal γδ-T-cells
In the periphery T cells are highly diverse and recognize a vast array of different antigens. In contrast, the mouse epidermis harbors a distinct population of T cells, the “invariant γδ-T-cells” with a very restricted antigen receptor repertoire. The antigen specificity is not known, but most likely these T cells recognize antigens released from stressed keratinocytes. γδ-T-cells are very important for maintaining a healthy skin, for wound healing and tumor surveillance. Moreover, they control bacterial skin infections by production of the cytokines IL17 and IL22. We found that these γδ-T-cells are almost completely absent in AhR-deficient mice, because they cannot proliferate in the skin after the initial seeding period in the neonatal mouse. We study how AhR signaling impact γδ-T-cells functions, especially in stressed skin. The knowledge gained will be used to identify ways to improve barrier functions in health and diseases. The project is done in cooperation with the Weighardt lab, and funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG103/7).
3. Oral tolerance
The gut associated immune system is composed of many and varied innate and adaptive immune cells. It is vital that immune cells in the gut protect against invading pathogens, but ignore food proteins (which in principle are antigens as well). The phenomenon is called “oral tolerance”. In our project we address the role of AhR for oral tolerance. This is particularly relevant in the context of food allergies, for the potential use in oral-tolerance based therapeutic approaches against autoimmune diseases, and for inflammatory bowel diseases. We showed in a standard mouse model of oral tolerance, that feeding dioxin (2,3,7,8-Tetrachlordibenzo-p-dioxin) before tolerance induction can break oral tolerance. We are now investigating whether an already established tolerance can be broken as well, and whether other AhR ligands than dioxin can influence tolerance as well. Of particular interest here are AhR ligands from plants, which are often dietary components, as there might be a link to food allergies. The project is funded by the “Deutsche Forschungsgemeinschaft“ (German Research Foundation, project ES103/6).
4. Regulation of the immunosuppressive enzyme IDO
It is very important that an immune reaction can be down-regulated or stopped once the danger is over, limiting tissue inflammation or adapting and fine-tuning a response. Several mechanisms of the immune system make sure of this. An important molecule in this context is the immunosuppressive enzyme IDO. Interestingly, IDO is a target gene of AhR and thus AhR contributes to immunoregulation. IDO metabolizes the amino acid tryptophan and the resulting metabolites (in particular the first metabolite, kynurenine) are AhR ligands. Kynurenines support the generation of regulatory T cells. In the skin, UV irradiation generates the high-affinity AhR ligand FICZ from the amino acid tryptophan, which may eventually set in motion also the IDO production. We investigate these complex interactions between external signals and AhR triggering, which contribute to the production of IDO by skin dendritic cells. We want to clarify the consequences of allergic and inflammatory reactions of the skin. The project is done in close collaboration with the Weighardt and Haarmann-Stemmann labs at IUF and supported by the “Deutsche Forschungsgemeinschaft” (German Research Foundation, project ES103/5).
The Esser lab is in charge of the central FACS and cell sorting unit of the IUF (leadership: Prof. Dr. C. Esser).
Haarmann-Stemmann junior research group
Haendeler research group
Krutmann research group
Ventura liaison research group
Weighardt liaison research group
Prof. Irmgard Förster, University Bonn,
Prof. Jan Hengstler, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund
Prof. Karin Loser, Clinic for skin diseases, Münster
Prof. Wilhelm Bloch, German Sport University Cologne
Prof. Karl Köhrer, Biological Medical Research Center at the University Düsseldorf
Prof. Raymond Pieters, University Utrecht, Netherlands
C, Rannug A: The Aryl Hydrocarbon Receptor in Barrier Organ Physiology,
Immunology, and Toxicology. Pharmacol Rev 67(2): 259-279, 2015.
Neumann C, Heinrich F, Neumann K, Junghans V, Mashreghi MF, Ahlers J, Janke M, Rudolph C, Mockel-Tenbrinck N, Kühl AA, Heimesaat MM, Esser C, Im SH, Radbruch A, Rutz S, Scheffold A: Role of Blimp-1 in programing Th effector cells into IL-10 producers. J Exp Med 211(9): 1807-1819, 2014. [pubmed]
Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334(6062): 1561-1565, 2011. [pubmed]
Kadow S, Jux B, Zahner SP, Wingerath B, Chmill S, Clausen BE, Hengstler J, Esser C: Aryl hydrocarbon receptor is critical for homeostasis of invariant gammadelta T cells in the murine epidermis. J Immunol 187(6): 3104-3110, 2011. [pubmed]
Chmill S, Kadow S, Winter M, Weighardt H, Esser C: 2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in mice. Toxicol Sci 118(1): 98-107, 2010. [pubmed] (open access)
Jux B, Kadow S, Esser C: Langerhans cell maturation and contact hypersensitivity are impaired in aryl hydrocarbon receptor-null mice. J Immunol 182(11): 6709-6717, 2009. [pubmed] (open access)