Esser research group: role of AhR in immuntoxicology
![Immunhistologische Mikroskopaufnahme der Epidermis einer Maus (links) und einer AhR-defizienten Maus (rechts) [grün gefärbt sind hautspezifische γδ-T-Zellen, rot gefärbt sind Langerhans-Zellen, d.h. die dendritischen Zellen der Epidermis]](system/html/Epidermis der Maus_AG Esser-76cb1ad7.jpg)
Head of research group:
Prof. Dr. rer. nat. Charlotte Esser 
Postdocs:
Dr. rer. nat. Katrin Hochrath
Dr. rer. nat. Nadine Teichweyde
Master students:
Lenny Paola Espinoza Luna
Manuel Schellner
Bachelor student:
Armin Ardeshirdavani
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.
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.[CK1] 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. 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[CK2] skin cells. Lack of AhR[CK3] 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[CK4] 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[CK5] 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).
Service
The Esser lab is in charge of the central FACS and cell sorting unit of the IUF (leadership: Prof. Dr. C. Esser).
[CK1]Dt. Version „und im Darm bei Exposition mit dem toxischen AhR-Liganden 2,3,7,8-Tetrachlorodibenzo-p-dioxin die orale Toleranz beeinflusst, die vor unerwünschten Immunreaktionen auf harmlose Nahrungsproteine schütz“
[CK2]Dt. Version „alle“
[CK3]Dt. Version „in Mäusen“
[CK4]Dt. Version „beenden“
[CK5]Dt. Version“ UV und Licht“
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.[CK1] 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. 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[CK2] skin cells. Lack of AhR[CK3] 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[CK4] 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[CK5] 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).
Service
The Esser lab is in charge of the central FACS and cell sorting unit of the IUF (leadership: Prof. Dr. C. Esser).
[CK1]Dt. Version „und im Darm bei Exposition mit dem toxischen AhR-Liganden 2,3,7,8-Tetrachlorodibenzo-p-dioxin die orale Toleranz beeinflusst, die vor unerwünschten Immunreaktionen auf harmlose Nahrungsproteine schütz“
[CK2]Dt. Version „alle“
[CK3]Dt. Version „in Mäusen“
[CK4]Dt. Version „beenden“
[CK5]Dt. Version“ UV und Licht“
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. Moreover,
the few remaining cells do not have the same number and lengths of dendrites as
in wild-type mice. With gene expression profiles, we showed 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 findings 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
IFNg. Finally, we are interested in identifying the role of γδ T cells in human skin,
and will develop relevant 3-D models for this.
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
Prof. Raymond Pieters, University Utrecht, Netherlands
Selected publications
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:
