Our research group utilizes in vivo models in order to unravel the complexities of AHR pathway regulation in health and disease.
The main focus of our group is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that belongs to the basic helix-loop-helix/PAS family of transcriptional regulators. The AHR has been studied extensively in the toxicology field because it mediates the toxic effects of the xenobiotic pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, AHR is highly conserved throughout evolution and its ability to recognize TCDD is thought to be a relatively recent evolutionary adaptation. It is now becoming clear that natural AHR ligands, such as certain dietary components and microbial metabolites, represent physiological activators of AHR with the capacity to modulate developmental processes, immunity and energy metabolism.
AHR pathway activation by natural ligands is tightly controlled and ligand binding to AHR leads to induction of cytochrome P4501 (CYP1) enzymes, which rapidly metabolize AHR ligands leading to signal termination. This potent negative feedback system ensures transient activation of AHR-dependent gene programs and means the AHR pathway is uniquely sensitive to alterations in ligand exposure. As such, AHR acts as a molecular decoder of dynamic environmental cues ranging from dietary nutrient composition and metabolic state to microbial metabolites. However, much remains to be learned about the physiological role of AHR ligands, and the mechanisms by which AHR activation results in functional changes on the cellular and organismal level.
Our research group utilizes in vivo models in order to unravel the complexities of AHR pathway regulation in health and disease. Our aim is to comprehensively answer the following questions:
- What are the cellular targets of AHR in health and disease?
- What are the molecular pathways downstream of AHR activation?
- What is the role of natural AHR ligands in health and disease?
We believe that a better understanding of AHR biology may facilitate the discovery of novel therapeutics for the treatment of chronic inflammatory diseases and metabolic syndrome.
Chris Schiering holds a Sir Henry Dale Fellowship.
Metidji A, Omenetti S, Crotta S, Li Y, Nye E, Ross E, Li V, Maradana MR, Schiering C*, and Stockinger B*. (2018). The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 49, 1-10.
*joint corresponding authors
Schiering C, Vonk A, Das S, Stockinger B, Wincent E. (2018). Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells. Biochem Pharmacol 151, 47-58.
Schiering C, Wincent E, Metidji A, Iseppon A, Li Y, Potocnik AJ, Omenetti S, Henderson CJ, Wolf CR, Nebert DW, Stockinger B. (2017). Feedback control of AHR signalling regulates intestinal immunity. Nature 542, 242-5.
Ilott NE, Bollrath J, Danne C, Schiering C, Shale M, Adelmann K, Krausgruber T, Heger A, Sims D, Powrie F. (2016). Defining the microbial transcriptional response to colitis through integrated host and microbiome profiling. ISME J 10, 2389-404.
Krausgruber T*, Schiering C*, Adelmann K, Harrison OJ, Chomka A, Pearson C, Ahern PP, Shale M, Oukka M, Powrie F. (2016). T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine. Nat Commun 7, 11627.
*joint first author
Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BM, Lohning M, Belkaid Y, Fallon PG, Powrie F. (2014). The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564-8.