WG Esser: Role of AhR in immuntoxicology

Epidermis der Maus

Immunohistological microscopy picture of the epidermis of a mouse (left) and an AhR-deficient mouse (right) [green staining: skin specific γδ-T-cells, red staining: Langerhans cells/epidermal dendritic cells]

Head of working group:
Prof. Dr. rer. nat. Charlotte Esser

Postdocs:
Dr. rer. nat. Natascha Künzel
Dr. rer. medic. Doreen Reichert
Dr. rer. nat. Nadine Teichweyde

Master student:
Fabienne Ruhmöller
Wenhao Xie

Technical assistance:
Babette Martiensen
Swantje Steinwachs

Research profile

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.

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).

Service

The Esser lab is in charge of the central FACS and cell sorting unit of the IUF (leadership: Prof. Dr. C. Esser).

Cooperations

IUF internal:
Haarmann-Stemmann research group
Krutmann research group
Schins research group
Ventura research group
Weighardt research group
Team Boukamp

National:
Prof. Irmgard Förster, University Bonn,
Prof. Karin Loser, Clinic for Skin Diseases, Münster
Prof. Stefan Janssen, University Giessen
Prof. Katja Ickstadt, TU Dortmund
Prof. Hyung-Dong Chan, DFRZ Berlin

International:
Prof. Christoph Vogel, UC Davis, USA
Prof. Myung-Shin Jeon, INCHEON University, Süd-Korea

Selected publications

Esser C: Trajectory shifts in interdisciplinary research of the aryl hydrocarbon receptor - a personal perspective on thymus and skin. Int J Mol Sci 22(4): 1844, 2021. doi: 10.3390/ijms22041844

Merches K, Schiavi A, Weighardt H, Steinwachs S, Teichweyde N, Förster I, Hochrath K, Schumak B, Ventura N, Petzsch P, Köhrer K, Esser C: AHR signaling dampens inflammatory signature in neonatal skin γδ T cells. Int J Mol Sci 21(6): 2249, 2020. doi: 10.3390/ijms21062249

Esser C, Hochrath K, Teichweyde N, Krutmann J, Chang H-D: Beyond sequencing: fast and easy microbiome profiling by flow cytometry. Arch Toxicol 93(9): 2703-2704, 2019. doi: 10.1007/s00204-019-02527-1

Hammerschmidt-Kamper C, Biljes D, Merches K, Steiner I, Daldrup T, Bol-Schoenmakers M, Pieters RHH, Esser C: Indole-3-carbinol, a plant nutrient and AhR-Ligand precursor, supports oral tolerance against OVA and improves peanut allergy symptoms in mice. Plos One 12(6): e0180321, 2017. doi: 10.1371/journal.pone.0180321

Haas K, Weighardt H, Deenen R, Köhrer K, Clausen B, Zahner S, Boukamp P, Bloch W, Krutmann J, Esser C: Aryl hydrocarbon receptor in keratinocytes is essential for murine skin barrier integrity. J Invest Dermatol 136(11): 2260-2269, 2016. doi: 10.1016/j.jid.2016.06.627

Esser C, Rannug A: The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol Rev 67(2): 259-279, 2015. (Review) doi: 10.1124/pr.114.009001

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. doi: 10.1126/science.1214914

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. doi: 10.4049/jimmunol.071334

TOP