Project Details
Projekt
Crosstalk between AHR signaling and retinoids in skin
Applicant
Professor Dr. Jean Krutmann
Subject Area
Dermatology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 495676076
Arylhydrocarbon receptor (AHR) signaling is critical for skin barrier function and photocarcinogenesis, which are also affected by retinoids. Retinoids are a family of signaling molecules which comprise vitamin A and its natural and synthetic derivatives. Under normal conditions, virtually all effects of vitamin A in the skin are mediated by all-trans retinoic acid (atRA). Formation of atRA involves as the final step the irreversible conversion of retinaldehyde to atRA by Aldehyde Dehydrogenase (ALDH) 1A enzymes, of which ALDH1A3 is the predominant isozyme in skin. Skin might be exposed to atRA as a consequence of its endogenous production by epidermal keratinocytes, but also after atRA has been topically applied for therapeutic or cosmetic indications. Of note, there is compelling evidence that retinoid signaling and AHR signaling can influence each other. All of these studies, however, have focused on non-cutaneous tissues and / or have employed the difficult to degrade AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) which causes long-lasting activation of AHR. It is currently not known how transient activation of AHR signaling by physiologically, environmentally or therapeutically and thus clinically relevant AHR ligands affects retinoid metabolism, how retinoids impact AHR signaling caused by such ligands, and how these interactions might be relevant for skin. In this regard, we have recently found that AHR signaling regulates synthesis of atRA in vitro in human keratinocytes and in vivo in murine skin. We also obtained evidence that AHR-induced regulation of the expression and activity of ALDH1A3 might be critically involved in this context. In addition, independent evidence suggests that a combined treatment of murine skin with atRA plus TCDD causes a proinflammatory, psoriasis-like inflammatory skin response. We therefore hypothesize that in skin, AHR signaling and retinoid signaling influence each other, that this interaction is bidirectional and of clinical relevance, e.g. for skin barrier function. Specifically, we will systematically assess AHR ligand-mediated regulation of atRA synthesis in epidermal keratinocytes, the role of ALDH1A3 as an AHR target gene in this process, the functional relevance of endogenous retinoid synthesis as an integral part of AHR responses in keratinocytes, and we will comprehensively characterize the crosstalk of exogenously added atRA and AHR ligands in skin. In all of these studies we will use transiently activating AHR ligands of clinical relevance. We will address these topics by employing genetically engineered keratinocytes, complete as well as conditional knockout mouse models, and ex vivo human skin models. This project contributes to a better understanding of AHR signaling in skin barrier function and its importance for clinically and cosmetically used topical retinoids.
DFG Programme
Research Units
Co-Investigator
Dr. Sonja Fassbender
