Aryl Hydrocarbon Receptor Expression in Serum, Peripheral Blood Mononuclear Cells, and Skin Lesions of Patients with Atopic Dermatitis and Its Correlation with Disease Severity
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent dermatitis and severe pruritus. The pathogenesis of AD involves abnormal immune responses and impaired skin barrier function. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has emerged as a key regulator in various physiological processes, including cell proliferation, apoptosis, differentiation, adhesion, and migration. AhR responds to exogenous and endogenous chemicals by inducing or repressing genes such as cytochrome P4501A1 (CYP1A1), which plays a role in detoxification and protection in various tissues. Recent studies have suggested that AhR expression is aberrantly induced in several skin diseases, including psoriasis and vitiligo. However, the role of AhR in AD remains poorly understood. This study aimed to investigate the expression of AhR and its downstream regulators in serum, peripheral blood mononuclear cells (PBMCs), and skin lesions of AD patients and to explore their correlation with disease severity.
Methods
The study was conducted at the Department of Dermatology, Peking University People’s Hospital, from August 1 to December 31, 2018. A total of 29 adult patients with AD were recruited based on the diagnostic criteria of Hanifin and Rajka and the Chinese criteria for AD. Exclusion criteria included treatment with systemic glucocorticoids or other immunosuppressive agents within the previous six weeks. Control subjects without allergic or chronic diseases were also recruited. The severity of AD was assessed using the eczema area and severity index (EASI) score.
Blood samples were collected from all participants under aseptic conditions. PBMCs were isolated using Ficoll Hypaque density gradient centrifugation. Total RNA was extracted from PBMCs using the RNA blood mini kit, and the mRNA levels of AhR, CYP1A1, AhR nuclear translocation (ARNT), and aryl hydrocarbon receptor repressor (AhRR) were measured using real-time quantitative polymerase chain reaction (RQ-PCR). Serum AhR levels were determined using enzyme-linked immunosorbent assay (ELISA). Skin biopsies were obtained from AD patients and control subjects, and AhR expression in skin lesions was assessed using immunohistochemistry.
Results
The study found that AhR expression was significantly higher in the serum and skin lesions of AD patients compared to controls. The mean serum AhR level in AD patients was 41.26 ± 4.52 pmol/L, compared to 33.73 ± 2.49 pmol/L in controls (t = 6.507, P < 0.001). In skin lesions, AhR expression was significantly higher in the epidermis of AD patients (0.191 ± 0.041) compared to controls (0.087 ± 0.017) (t = 10.036, P < 0.001). AhR was also expressed in endothelial cells of blood vessels and infiltrating inflammatory cells, primarily lymphocytes, in the dermis of AD patients.
In PBMCs, the mRNA levels of AhR, AhRR, and CYP1A1 were significantly higher in AD patients compared to controls. The relative mRNA expression of AhR was 1.572 ± 0.392 in AD patients versus 1.000 ± 0.173 in controls (t = 6.819, P < 0.001). Similarly, AhRR expression was 2.402 ± 1.716 in AD patients compared to 1.000 ± 0.788 in controls (t = 3.722, P < 0.001), and CYP1A1 expression was 2.258 ± 1.598 in AD patients versus 1.000 ± 0.796 in controls (t = 3.400, P = 0.002). However, there was no significant difference in the mRNA levels of ARNT between AD patients and controls (1.383 ± 0.842 vs. 1.000 ± 0.586, t = 1.653, P = 0.105).
The study also found a positive correlation between AhR mRNA levels in PBMCs and disease severity, as measured by the EASI score (r = 0.448, P = 0.019). Additionally, AhR mRNA levels in PBMCs positively correlated with serum interleukin-6 (IL-6) levels (r = 0.377, P = 0.046). The expression of AhRR in PBMCs also showed a significant positive correlation with serum IL-1β levels (r = 0.467, P = 0.021).
Discussion
The findings of this study suggest that AhR and its downstream regulators are highly expressed in the serum, PBMCs, and skin lesions of AD patients, and that these expressions correlate with disease severity. AhR is a transcription factor that plays a crucial role in regulating xenobiotic metabolism and various physiological processes. It is activated by ligands such as dioxins, flavonoids, and tryptophan photoproducts, leading to its translocation into the nucleus, where it dimerizes with ARNT to form a transcription factor complex. This complex binds to xenobiotic-responsive elements (XREs) in the DNA, inducing the transcription of genes such as CYP1A1 and AhRR.
CYP1A1 is a well-known downstream regulator of AhR, primarily involved in the detoxification of hydrocarbons. AhRR, on the other hand, acts as a negative regulator of AhR signaling by binding to corepressors and inhibiting the transcription of AhR-dependent genes. The increased expression of AhR, CYP1A1, and AhRR in AD patients suggests that the AhR signaling pathway is activated in AD and may contribute to its pathogenesis.
The positive correlation between AhR mRNA levels in PBMCs and disease severity, as measured by the EASI score, further supports the role of AhR in AD. Additionally, the correlation between AhR mRNA levels and serum IL-6 levels suggests that AhR may modulate inflammatory responses in AD. IL-6 is a pro-inflammatory cytokine that plays a key role in the pathogenesis of AD, and its regulation by AhR may be one of the mechanisms through which AhR contributes to the disease.
The expression of AhR in the epidermis of AD patients was significantly higher than in controls, suggesting that AhR may play a role in the regulation of keratinocyte differentiation and skin barrier function. In normal skin, AhR is primarily expressed in the basal layer of the epidermis, whereas in AD patients, it is expressed throughout the epidermis, particularly in the granular layers. This increased expression may contribute to the impaired skin barrier function observed in AD patients.
The study also found that AhR was expressed in endothelial cells of blood vessels and infiltrating inflammatory cells in the dermis of AD patients. This suggests that AhR may also play a role in the regulation of vascular function and immune responses in AD. The expression of AhR in inflammatory cells, primarily lymphocytes, further supports its role in modulating immune responses in AD.
The findings of this study are consistent with previous studies that have reported increased expression of AhR in other inflammatory skin diseases, such as psoriasis and vitiligo. However, the role of AhR in these diseases is complex and may involve both pro-inflammatory and anti-inflammatory effects. In healthy skin, AhR signaling driven by endogenous ligands can regulate keratinocyte differentiation and skin barrier function, reducing skin inflammation. However, in the presence of xenobiotic AhR ligands, canonical signaling may dominate, leading to adverse effects such as impaired epidermal barrier function, cytokine release, oxidative stress, and cancer promotion.
The study has some limitations. The sample size was relatively small, and the study was conducted at a single center, which may limit the generalizability of the findings. Additionally, the study did not investigate the effects of AhR ligands on the expression of AhR and its downstream regulators in AD patients. Further studies are needed to explore the mechanisms through which AhR contributes to the pathogenesis of AD and to evaluate the potential therapeutic effects of AhR modulation in AD.
In conclusion, this study provides new evidence that the AhR signaling pathway is involved in the pathogenesis of AD. The increased expression of AhR and its downstream regulators in the serum, PBMCs, and skin lesions of AD patients, and their correlation with disease severity, suggest that AhR may play a key role in the regulation of immune responses and skin barrier function in AD. Further studies are needed to explore the therapeutic potential of targeting the AhR signaling pathway in AD.
doi.org/10.1097/CM9.0000000000000591
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