Our group studies the complex interplay between environment, inflammation and metabolism with a particular focus on the gastrointestinal tract.
Environmental factors, such as diet and microbiota, are important modulators of physiology. However, little is known about how these signals are integrated at the cellular and molecular level. To shed light on this, we investigate the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor capable of sensing dietary components and microbial metabolites. We and others have demonstrated that genetic deficiency in AHR is associated with compromised intestinal barrier integrity, altered microbiota composition and dysregulated host responses to pathogens and injury. Importantly, genome-wide association studies have identified AHR as susceptibility locus in inflammatory bowel disease, highlighting the relevance of this pathway to human pathology.
AHR pathway activation 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 axis ensures transient activation of AHR-dependent gene programs, creating a signalling pathway uniquely sensitive to temporal fluctuations in ligand exposure. As such, AHR can be regarded as a dynamic molecular decoder of a wide variety of environmental cues.
Our group aims to characterise and harness the therapeutic potential of AHR pathway modulation through the use of preclinical disease models, epigenetic profiling and scRNA-seq technologies. We believe that a better understanding of AHR biology may facilitate the discovery of novel treatments for chronic inflammatory diseases.
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.