AHR and NRF2 in Skin Homeostasis and Atopic Dermatitis

Abstract

Skin is constantly exposed to environmental insults, including toxic chemicals and oxidative stress. These insults often provoke perturbation of epidermal homeostasis and lead to characteristic skin diseases. AHR (aryl hydrocarbon receptor) and NRF2 (nuclear factor erythroid 2-related factor 2) are transcription factors that induce a battery of cytoprotective genes encoding detoxication and antioxidant enzymes in response to environmental insults. In addition to their basic functions as key regulators of xenobiotic and oxidant detoxification, recent investigations revealed that AHR and NRF2 also play critical roles in the maintenance of skin homeostasis. In fact, specific disruption of AHR function in the skin has been found to be associated with the pathogenesis of various skin diseases, most prevalently atopic dermatitis (AD). In this review, current knowledge on the roles that AHR and NRF2 play in epidermal homeostasis was summarized. Functional annotations of genetic variants, both regulatory and nonsynonymous SNPs, identified in the AHR and NRF2 loci in the human genome were also summarized. Finally, the possibility that AHR and NRF2 serve as therapeutic targets of AD was assessed.

Genetic/Environmental Contributions and Immune Dysregulation in Children with Atopic Dermatitis

“…Tapinarof may outcompete toxigenic ligands for AHR binding, resulting in downregulation of proinflammatory cytokines and normalization of the skin barrier. 225 , 254 , 255 Meanwhile, increasing recognition of the role of the microbiome in AD may lead to new therapies to re-balance pathogens and commensals on the skin. Cutaneous microbial transplantation and vaccines against S. aureus are two nascent strategies.…”

“… 224 Regarding a mechanism for air pollution-induced AD, PM contains polycyclic hydrocarbons (PAHs) that may activate AHR. 225 In fact, treatment of human skin equivalents and murine skin with PM2.5 inhibits FLG protein expression via PM2.5-induced TNF-α and is AHR-dependent. 226 As discussed above, AHR activation may also increase artemin expression and itch.…”

NRF2 in dermo‐cosmetic: From scientific knowledge to skin care products

“…CYP), as well as proteins involved in epidermic differentiation (filaggrin, loricrin, involucrin) 61 . However, AhR has a binding site in the XRE (Xenobiotic Response Element) promoter of Nrf2 and in return, Nrf2 has a site in the AhR promoter 62 . This crosstalk between Nrf2 and AhR influences the quality of the barrier function, particularly in the context of stress or skin disease such as atopic dermatitis (AD).…”

“…61 However, AhR has a binding site in the XRE (Xenobiotic Response Element) promoter of Nrf2 and in return, Nrf2 has a site in the AhR promoter. 62 This crosstalk between Nrf2 and AhR influences the quality of the barrier function, particularly in the context of stress or skin disease such as atopic dermatitis (AD). AD is an inflammatory dermatological condition with a multifactorial origin: genetic determinism (mutation in the filaggrin gene for example), extreme sensitivity to environmental impacts (dryness, cold, pollution, and oxidative stress), imbalance in the skin microbiome, and so forth.…”

Oxidative Stress and Phototherapy in Atopic Dermatitis: Mechanisms, Role, and Future Perspectives

“…In fact, single nucleotide polymorphisms (SNPs) of the AHR gene, modifying the activity of this receptor and its antioxidant capacity, correlate with an increased risk of the onset of AD. No relationship between NRF2 SNPs with AD pathogenesis has been found [ 21 ]. However, the AHR/ARNT axis appears to be involved in the development of pruritus in AD since the ARNT gene encodes the neurotrophic factor artemin responsible for epidermal hyperinnervation and pruritus [ 18 ].…”