International Journal of Molecular Sciences Review A New Insight into the Potential Role of Tryptophan-Derived AhR Ligands in Skin Physiological and Pathological Processes Monika Szelest †,‡ , Katarzyna Walczak *,† and Tomasz Plech Department of Pharmacology, Medical University of Lublin, Chod´zki4a, 20-093 Lublin, Poland; [email protected] (M.S.); [email protected] (T.P.) * Correspondence: [email protected]; Tel.: +48-81-448-6774 † These authors contributed equally to this work. ‡ A Volunteer in the Department of Pharmacology, Medical University of Lublin. Abstract: The aryl hydrocarbon receptor (AhR) plays a crucial role in environmental responses and xenobiotic metabolism, as it controls the transcription profiles of several genes in a ligand- specific and cell-type-specific manner. Various barrier tissues, including skin, display the expression of AhR. Recent studies revealed multiple roles of AhR in skin physiology and disease, includ- ing melanogenesis, inflammation and cancer. Tryptophan metabolites are distinguished among the groups of natural and synthetic AhR ligands, and these include kynurenine, kynurenic acid and 6-formylindolo[3,2-b]carbazole (FICZ). Tryptophan derivatives can affect and regulate a variety of signaling pathways. Thus, the interest in how these substances influence physiological and patholog- ical processes in the skin is expanding rapidly. The widespread presence of these substances and potential continuous exposure of the skin to their biological effects indicate the important role of AhR and its ligands in the prevention, pathogenesis and progression of skin diseases. In this review, we summarize the current knowledge of AhR in skin physiology. Moreover, we discuss the role of AhR in skin pathological processes, including inflammatory skin diseases, pigmentation disorders and Citation: Szelest, M.; Walczak, K.; cancer. Finally, the impact of FICZ, kynurenic acid, and kynurenine on physiological and pathological Plech, T. A New Insight into processes in the skin is considered. However, the mechanisms of how AhR regulates skin function the Potential Role of require further investigation. Tryptophan-Derived AhR Ligands in Skin Physiological and Keywords: aryl hydrocarbon receptor; tryptophan; kynurenine; FICZ; skin; kynurenic acid; atopic Pathological Processes. Int. J. Mol. Sci. dermatitis; psoriasis; melanoma 2021, 22, 1104. https://doi.org/ 10.3390/ijms22031104 Received: 29 November 2020 1. Introduction Accepted: 19 January 2021 Published: 22 January 2021 The aryl hydrocarbon receptor (AhR) is expressed in various tissues characterized by a rapid growth rate, including skin [1]. Gene expression analysis revealed that AhR activation enhances or suppresses the expression of several genes, thus influencing the gene Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in expression profile [2]. Previous studies revealed the crucial role of AhR in several physio- published maps and institutional affil- logical and pathological processes in the skin. Among the groups of natural and synthetic iations. AhR ligands is the group of tryptophan derivatives [1,3]. Some of them, including kynure- nine, kynurenic acid, and 6-formylindolo[3,2-b]carbazole (FICZ), have been previously recognized as ligands of this receptor. However, recently discovered biological properties of these substances, their widespread presence, and potential continuous exposure may suggest the important role of tryptophan-derived AhR ligands in many physiological and Copyright: © 2021 by the authors. pathological processes in the skin [4]. Unfortunately, the role of AhR itself and the biological Licensee MDPI, Basel, Switzerland. This article is an open access article effect of the tryptophan-derived ligands in the prevention, pathogenesis, and progression distributed under the terms and of skin diseases are not fully understood to date. conditions of the Creative Commons 2. Aryl Hydrocarbon Receptor (AhR) Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ AhR is a transcription factor from the evolutionarily old family of a basic helix-loop- 4.0/). helix/Per-ARNT-Sim (bHLH-PAS) transcription regulators, acting in a DNA sequence- Int. J. Mol. Sci. 2021, 22, 1104. https://doi.org/10.3390/ijms22031104 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 30 Int. J. Mol. Sci. 2021, 22, 1104 2. Aryl Hydrocarbon Receptor (AhR) 2 of 31 AhR is a transcription factor from the evolutionarily old family of a basic helix-loop- helix/Per-ARNT-Sim (bHLH-PAS) transcription regulators, acting in a DNA sequence- specificspecific manner.manner. The bHLH motif contains two domains that areare responsibleresponsible forfor DNADNA sequence bindingbinding andand proteinprotein dimerizationdimerization [[1].1]. SeveralSeveral low-molecular-weightlow-molecular-weight chemicalchemical compounds activateactivate thethe cytosoliccytosolic AhRAhR afterafter enteringentering cellscells viavia diffusiondiffusion [[3,5].3,5]. AirAir pollutionpollution compounds [[3],3], endogenousendogenous amino amino acid acid derivatives derivatives [6 –[6–8],8], some some food food components components (e.g., (e.g., in- doles,indoles, polyphenols, polyphenols, glucosinolates) glucosinolates) [9 [9–11],–11], and and some some yeast yeast and and bacterial bacterial metabolites metabolites [[12]12] are considered AhR ligands. ligands. AhR AhR has has only only one one binding binding pocket, pocket, whose whose amino amino acid acid compo- com- positionsition determines determines ligand ligand binding binding strength strength [1]; [1 however,]; however, AhR AhR may may also also be be activated activated by by a anumber number of of stress stress factors factors and and some some substances substances that that might might not not fit fit into the bindingbinding pocketpocket (e.g.,(e.g., hypoxiahypoxia andand oxidizedoxidized low-densitylow-density lipoproteins)lipoproteins) [[13].13]. The type of AhR ligand determinesdetermines thethe levellevel ofof activationactivation andand thethe spectrumspectrum ofof genesgenes transcribedtranscribed [[14–16].14–16]. An increased AHR expression is observed in the placenta, placenta, liver, lungs, intestines,intestines, and and skin, skin, which which are are barrier barrier tissues tissues or orplay play an animportant important role role in metabolism. in metabolism. The Thelowest lowest AHRAHR expressionexpression is reported is reported in the in thebrain, brain, kidneys, kidneys, and and skeletal skeletal muscles muscles [2]. [Recent2]. Re- centstudies studies revealed revealed additional additional functions functions of AhR of AhR in inthe the body, body, including including control control of of liver andand vascularvascular development, intestinal immunity, hematopoiesis,hematopoiesis, and perinatal growth [17–22]. [17–22]. Moreover, AhRAhR signalingsignaling maymay bebe associatedassociated withwithstem stemcell cell proliferation proliferation and and carcinogene- carcinogen- sisesis [ 2[2].]. After ligand binding, binding, AhR AhR di dissociatesssociates from from its its chaperones chaperones (e.g., (e.g., proto-oncogene proto-oncogene ty- tyrosine-proteinrosine-protein kinase kinase c-Src, c-Src, heat heat shock shock protei proteinn 90 (HSP90), 90 (HSP90), p23, p23,and the and hepatitis the hepatitis B virus B virusX-associated X-associated protein protein 2 (XAP2)) 2 (XAP2)) and undergoes and undergoes conformational conformational changes, changes, resulting resulting in the inexposition the exposition of the nuclear of the nuclear translocation translocation signal and signal induction and induction of AhR of transport AhR transport into the into nu- thecleus nucleus (Figure (Figure 1A) [23].1A) [23]. Figure 1. Schematic overview overview of of aryl aryl hydrocarbon hydrocarbon receptor receptor (AhR) (AhR) signaling signaling pathways: pathways: canonical canonical (A) and noncanonical(A) and noncanonical (B). In physiological (B). In physiological conditions, AhRconditions, is localized AhR in is the localized cytosol in and the complexed cytosol and with com- specific proteins,plexed with such specific as the hepatitis proteins, B virussuch X-associatedas the hepati proteintis B virus 2 (XAP-2), X-associated heat shock protein protein 2 (XAP-2), 90 (HSP90), heat c-Src andshock p23. protein Upon 90 ligand (HSP90), binding, c-Src AhR and changes p23. Upon its conformation ligand binding, and isAhR translocated changes toits the conformation nucleus, where and it dimerizes with AhR nuclear transporter (ARNT) (A) or other partners, such as transcription factors (e.g., Kruppel-like factor 6 (KLF6)). (B). Dissociated c-Src interacts with the epidermal growth factor receptor (EGFR). To date, several different types of crosstalk between AhR and other proteins have been described. Int. J. Mol. Sci. 2021, 22, 1104 3 of 31 For instance, AhR interaction with the hyperphosphorylated form of the retinoblastoma protein (Rb) results in growth arrest at the G1/S phase of the cell cycle [24]. AhR signaling may also pro- mote nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation via RelA and RelB interaction [25–27]. Moreover, AhR signaling is associated with the activity and function of the estrogen receptor [28]. The AhR/ARNT complex binds to the xenobiotic-responsive element (XRE) and induces the transcription of AhR-responsive genes (e.g., CYP1A1). On the other hand, AhR ligation promotes the transcription of its