Abstract
Atopic dermatitis (AD) is characterized by skin barrier disruption, type 2 immune dysregulation, chronic pruritus, and abnormal colonization by Staphylococcus aureus (S. aureus). Tapinarof, an aryl hydrocarbon receptor modulator, has been demonstrated to attenuate the development of AD in clinical studies. Recently, we found that tapinarof upregulated the expression of filaggrin and loricrin, which are essential proteins in skin barrier functions. Paradoxically, tapinarof induced interleukin (IL)-24 secretion by normal human keratinocytes. IL-24 is produced by T helper 2 lymphocytes and keratinocytes following stimulation by type 2 cytokines, and IL-24 is upregulated in the skin of patients with AD. Furthermore, IL-24 contributes to skin barrier disruption and hyperplasia in AD, and it may exacerbate skin inflammatory responses, itch, and S. aureus infection. In this review, we summarized the current findings regarding the detrimental role of IL-24 in AD, thereby suggesting that co-treatment of tapinarof with therapeutics that block IL-24 signaling may represent a promising strategy for managing AD.
Highlights
Atopic dermatitis (AD), a common inflammatory skin disease, is associated with significant physiopsychological and socioeconomic burdens in affected patients [1]
interleukin-24 Janus kinase (JAK) (IL-24) is produced by T helper 2 lymphocytes and keratinocytes following stimulation by type 2 cytokines, and IL-24 is upregulated in the skin of patients with AD
Some studies determined that IL-24 is the target cytokine of some oxidative environmental aryl hydrocarbon receptor (AHR) agonists, such as 2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin (TCDD), benzo(a)pyrene, particulate matter, and ultraviolet B irradiation, in primary human chorionic stromal cells, human lung adenocarcinoma cells, normal human bronchial epithelial cells, and normal keratinocytes, respectively [15, 18,19,20,21]. In line with these findings, we recently demonstrated that tapinarof, an antioxidative AHR modulator [22], stimulated normal human epidermal keratinocytes to generate IL-24 protein, whereas AHR depletion significantly attenuated the upregulation of IL-24 induced by tapinarof [7]
Summary
Atopic dermatitis (AD), a common inflammatory skin disease, is associated with significant physiopsychological and socioeconomic burdens in affected patients [1]. We demonstrated that tapinarof upregulated the expression of filaggrin (FLG) and loricrin (LOR), which are important skin barrier-related proteins. IL-24 expression is upregulated in the epidermis in patients with AD [8, 9], its implications in the pathogenesis of AD remain poorly investigated. IL-24 protein expression was upregulated from the basal layer to the spinous cell layer, but not in the granular and cornified layers, in the epidermis of skin tissues from patients with AD [9]. No data have been presented regarding IL-24 serum levels in patients with AD; the serum levels of this cytokine did not differ between IL-4 transgenic and wild-type mice, suggesting the local role of IL-24 in AD pathophysiology [8]. IL-24 can be produced by immune cells, including monocytes, macrophages, mast cells, natural killer cells, and T and B lymphocytes, as well as non-immune cells, such as keratinocytes and melanocytes, in response to certain stimuli [10, 11] (Figure 1)
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