AhR receptor

The aryl hydrocarbon receptor, AhR for short, is encoded by the AhR gene, which is localized on chromosome 7p21.1. The aryl hydrocarbon receptor is an evolutionarily ancient, highly conserved cytoplasmic protein that is expressed by all cells of the epidermis.
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-dependent transcription factor that is expressed in various types of skin cells (keratinocytes, fibroblasts, mast cells and melanocytes). In healthy skin, AhR signaling is critical for maintaining skin homeostasis by regulating the skin's immunological network, keratinocyte differentiation, skin barrier function and gene expression in cells (Smith SH et al. 2017; Napolitano M et al. 2018).

The aryl hydrocarbon receptor can bind to endogenous or exogenous substances such as pollutants, polycyclic aromatic hydrocarbons (PAHs), microbial products, dietary ligands and phytochemicals (Di Meglio P et al. 2014). When one of these ligands binds to the receptor, the AhR-ligand complex migrates to the nucleus and dimerizes through the AhR nuclear translocator (ARNT). The AhR ligand-ARNT complex binds to specific DNA recognition sites and triggers gene transcription (Fernández-Gallego N et al. 2021).

The aryl hydrocarbon receptor (AhR) is present in non-active form in the cytosol in a complex with other proteins (hsp90, AIP, p23). It can bind to endogenous or exogenous substances such as pollutants, polycyclic aromatic hydrocarbons (PAHs), microbial products, ligands from food and secondary plant substances (Di Meglio P et al. 2014). When one of these ligands binds to the receptor, the AhR-ligand complex migrates into the cell nucleus and dimerizes through the AhR nuclear translocator (ARNT - (Ah receptor nuclear translocator - see ARNT gene below). The AhR ligand-ARNT complex binds to specific DNA recognition sites and triggers gene transcription (Fernández-Gallego N et al. 2021).

Among other things, it has been shown that this receptor regulates enzymes that metabolize xenobiotics, such as cytochrome P450 (Ema M et al. 1994). In principle, it is a ligand-activated transcription factor that enables cells to adapt to changing conditions by sensing compounds from the environment, diet, microbiome and cell metabolism, and plays an important role in development, immunity and tumor entities (MacPherson L et al. 2013; Ema M et al. 1994). In addition to xenobiotics, natural ligands derived from plants, microbiota and endogenous metabolism are potent AHR agonists. Tryptophan (Trp) derivatives represent an important class of endogenous AHR ligands (Sadik A et al. 2020).the AhR protein receptor inhibits the gene expression of proinflammatory cytokines such as IL-17A, IL17-/ as well as Il-4 and Il-13.

Furthermore, the AhR transcription factor regulates a variety of biological processes, including angiogenesis, hematopoiesis, drug and lipid metabolism, cell motility and immunomodulation.

The AhR functional axis is important for the maintenance of immune tolerance and the development of specific immune subsets, highlighting the potential role of AhR in PD-1 immunobiology. Understanding the functions of AhR ligands as well as the interaction of AhR with STAT1, NF-kappaB and EBV may provide insights into disease development, the PD-1 axis and immunotherapies targeting PD-1 and its ligand PD-L1.

Remarkably, Malassezia furfur is able to alter skin pimaging via malacessin, a natural ligand of AhR.

It is noteworthy that Malazessia furfur is able to alter skin pimaging via malacessin, a natural ligand of the AhR.

AhR plays a role in the pathogenesis of inflammatory skin diseases. Two AhR signaling pathways have been described:

• the canonical activation pathway (AHR: ARNT signaling pathway), which induces carcinogenesis and hyperpigmentation and inhibits apoptosis
• the non-canonical AhR pathway (includes other signaling pathways such as EGFR, MAPK, NF-kappaB, STATs and NRF-2), which induces inflammation, abnormal barrier function, hypopigmentation, cytokine production and reactive oxygen species. This signaling pathway has been identified as a potential therapeutic target (Haarmann-Stemmann T et al. 2015).

AhR and psoriasis: In psoriatic skin, the aryl hydrocarbon receptor is present in skin plaques and regulates the inflammatory response as well as the terminal differentiation of keratinocytes and T lymphocytes. In vitro and in vivo studies have shown that AhR deficiency leads to an increased responsiveness to proinflammatory stimuli and the development of uncontrolled inflammation. AhR-deficient mice showed pronounced psoriasiform skin inflammation with increased IL-17 and IL-22 production in an imiquimod-induced psoriasis model compared to controls. In addition, dysregulation of keratinocytes and fibroblasts was also observed in the deficient mouse skin models. However, IL-17 is not the only cytokine involved in the development of psoriasiform inflammation in the AhR-deficient mouse model, as inflammation was not attenuated by blocking IL-17 (Di Meglio P et al. 2014).

Ah receptors and UV irradiation of the skin: It has been shown that the Ah receptor plays a central role in the initiation of internal signaling cascades after UVB irradiation. In epidermal keratinocytes, UVB irradiation leads to various tryptophan-containing photoproducts. These photoproducts, along with other aromatic hydrocarbons, are natural ligands of the Ah receptor and lead to its activation. In the subsequent signalling cascade, there is an upregulation of inflammation-associated genes such as COX-2, which in turn increase the expression of metalloproteinases such as MMP-1 and MMP-3. Furthermore, melanocyte proliferation and melanin synthesis are triggered. The activation of the Ah receptor also plays an important role in the development of Treg and gamma-delta T cells; this could have an impact on immunological reactions.

The AhR agonist Tapinorof is a cream application for the treatment of psoriasis and atopic dermatitis (approved in the USA and China).

1. Di Meglio P et al. (2014) Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity 40:989-1001.
2. Ema M et al. (1994) Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J Biol Chem 269:27337-2743
3. Fernández-Gallego N et al. (2021) Role of AHR ligands in skin homeostasis and cutaneous inflammation. Cells 10:3176.
4. Furue M et al. (2019) Aryl hydrocarbon receptor in atopic dermatitis and psoriasis. Int J Mol Sci 20:5424.
5. Haarmann-Stemmann T et al. (2015) The Janus-faced role of aryl hydrocarbon receptor signaling in the skin: consequences for prevention and treatment of skin disorders. J Invest Dermatol 135:2572-2576.
6. Haarmann-Stemmann T et al. (2021) The mode of action of tapinarof may not only depend on the activation of cutaneous aryl hydrocarbon receptor signaling but also on its antimicrobial activity. J Am Acad Dermatol 85:e33-e34.
7. Napolitano M et al. (2018) Aryl hydrocarbon receptor (AhR) a possible target for the treatment of skin disease. Med Hypotheses 116:96-100.
8. Puga A et al (2002). Role of the aryl hydrocarbon receptor in cell cycle regulation. Chem Biol Interact 141:117-130.
9. Sadik A et al. (2020) IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell 182:1252-1270.
10. Schulte KW et al. (2017) Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene Activation. Structure 25:1025-1033
11. Smith SH et al. (2017) Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J Invest Dermatol 137:2110-2119.