Atopic dermatitis (AD) is a multifactorial disease with significant interactions among genetic susceptibility(1), impaired skin barrier(2), immune perturbation (3), and environmental exposures(4). While other investigators have found that indoor and outdoor air pollution is associated with AD, we have reported lifetime smoking exposure increases the risk of adult-onset AD(5). Protein sensitization represents an initial step in AD development(6, 7). The aryl hydrocarbon receptor (AhR) acts an environmental sensor regulating immune responses. In kin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). We reported that AhR activation by benzopyrenes (BP), a major PAH in smoke, is accentuated in AD skin. In mice, BP increases LC migration in vivo, and increases Th2 cytokines during in vitro challenge through AhR(8). However, how AhR activates or inhibits cutaneous immune responses remain controversial, likely due to the differential cell-specific functions of AhR. For example, AhR in keratinocytes links AD and air pollution via neurotrophic factor artemin(9). Therefore, we sought to investigate the immunoregulatory role of AhR in LC. We generated Langerin-specific mice lacking AhR in LC and tested them in epicutaneous protein sensitization. We showed that Langerin-AhR-/- mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Deletion of AhR in LC diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses.(10)
　　Current topical treatment for AD includes topical steroid, calcineurin inhibitors, and phosphodiesterase 4 (PDE4) inhibitor. Topical steroid is effective for AD but its long-term use results in skin atrophy, telangiectasis, and infections. Calcineurin inhibitors is moderately effective without these adverse effects, however, application site irritancy nd backbox warning for cutaneous lymphoma should be considered. Topical PDE4 inhibitor is also moderately effective without side effects of topical steroid, although it still carries a slightly increased application site irritancy. Therapeutically targeting AhR, coal tar induces keratinocyte-derived antimicrobial peptides via AhR(11), not only to treat skin dysbiosis, but also restore skin barrier(12). Glyteer soybean tar, an AhR ligand, improves AD by impairing IL-31 axis in DC(13). A recent phase 2b trial for topical tapinarof cream (an AhR modulating agent) for AD showed its efficacy and good tolerability without significant difference of application site irritation. Although larger prospective studies are required, targeting AhR could be a potential important advance in topical medicine development for AD(14).
References
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