Vitiligo is a common disease that approximately affects 0.5% of the population worldwide, and more than half of the patients develop the disease between the ages of 10 and 30 years. Although genetic susceptibility, environmental triggers, oxidative stress, autoimmunity and neural hypothesis are recognized as the pathogenic factors, the pathogenesis of vitiligo is incompletely clarified and there is no satisfactory therapy available right now. Vitiligo is an autoimmune condition characterized by the death of melanocytes due to immunological cytotoxicity or cell death caused by oxidative stress Immunosuppressive medications, such as topical tacrolimus, topical ruxolitinib, and narrow-band UV therapy, can be used to achieve repigmentation. Within the proposed molecular mechianism for this disease, scientists now focus on aryl hydrocarbon receptor (AhR), a nuclear transcription factor activated by exogenous and endogenous ligands.
The AhR/ARNT complex recognizes xenobiotic regulative elements (XREs) and mediates numerous toxicological or biological effects by modulating the transcription of various downstream genes. Besides, AhR can also regulate the gene expression through non-canonical signaling pathways, such as nuclear factor-κB (NF-κB), Krüppel-like factor 6 (KLF6) and the estrogen receptor (ER-alpha). Accumulating evidence has evinced that AhR is highly expressed in the skin and plays important roles in regulating epidermal barrier differentiation, cellular homeostasis, pigment synthesis and skin immunity. Recent studies identified abnormal AhR expression in vitiligo. Rekik et al. found decreased AhR transcription in the lesional skin of vitiligo. Wang et al. showed that decreased AhR expression in peripheral blood mononuclear cells of vitiligo patients was closely associated with the disease severity.
Prior research has demonstrated the involvement of the cytokines IL-17A and IL-22 in the progression of vitiligo. The AhR plays a role in the development of vitiligo and has the ability to regulate the production of cytokines. In vitiligo, Liu et al. conducted a study to investigate the connection between AhR activation and CD4+ T cell secretion of IL-17A and IL-22. A cohort of 20 individuals recently diagnosed with progressing, unstable vitiligo and 20 individuals without any health conditions were selected for the study. CD4+ T cells and skin samples were collected. Scientists employed several molecular biology techniques to find that AhR expression was markedly reduced in the CD4+ T cells and skin, including both lesional and non-lesional areas, of vitiligo patients in comparison to healthy individuals. The expression of AhR was significantly reduced in non-lesional skin of patients with vitiligo compared to their lesional skin.
Patients with vitiligo exhibited markedly elevated expression levels of IL-17A and IL-22 in comparison to healthy individuals. Suppression of AhR resulted in a substantial rise in the production of IL-17A and a considerable decrease in IL-22 levels in the CD4+ T cells of vitiligo patients. Therefore, a decrease in AhR expression is linked to the advancement and instability of vitiligo. Tapinarof is a topical nonsteroidal immune modulating agent, first developed by Welichem Biotech Inc. It has been demonstrated to be effective in humans for treatment of atopic dermatitis and psoriasis. It has recently received regulatory approval as a topical psoriasis therapy in China (2019) and the United States (2022). It is an agonist of AhR, which is involved in suppressing immune response and inhibiting oxidative stress. Hence, tapinarof has the potential to exert positive effects on vitiligo by inhibiting the two processes responsible for melanocyte death.
Tapinarof has been shown to inhibit immune-activating cytokines and reduce oxidative stress by activating the expression of Nrf2 transcription factor. Considering the postulated involvement of these two routes in melanocyte death in vitiligo, it is not surprising that tapinarof could potentially treat individuals with vitiligo. Given that topical tapinarof has demonstrated the capacity to cause long-term remission of psoriasis and possesses the capability to diminish the production of memory T cells, which play a role in the development of vitiligo, it is plausible that it might likewise prompt long-term remission in vitiligo.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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