Targeting the Aryl Hydrocarbon Receptor to Address the Challenges of Atopic Dermatitis

dietary, xenobiotic, and environmental sources.^1,19-21 Depending on the ligand and cellular context, AhR signaling results in the induction or repression of different genes with diverse responses in a wide range of tissues.¹  

Ligand-dependent AhR activation induces cytoprotective responses in the skin by upregulating antioxidant pathways and skin-barrier protein and ceramide lipid production.^1,14,22 After AhR binds to a ligand in the cytoplasm, conformational changes result in nuclear translocation,^23,24 where the AhR-ligand complex heterodimerizes with AhR nuclear translocator (ARNT) and binds to specific DNA recognition sites to control transcription of AhR-responsive genes.^23,24 

Classical AhR signaling pathways were initially elucidated in determining the toxicologic effects of polycyclic aromatic hydrocarbons, which may explain the association between atmospheric pollution and AD and asthma.^25-28 In addition to regulating gene expression as a nuclear receptor, AhR interacts with other genes and proteins to modulate genomic and cytosolic pathways.²⁹ 

In vitro, ex vivo, and in vivo models point to a key role for AhR as a regulator of homeostasis in immune and epithelial cells, via multiple pathways, including alteration of the transcriptional program of regulatory T (Treg) cells and epithelial cells.³⁰ AhR also signals through Nrf2 to induce cytoprotective antioxidant responses, and mediates antioxidative and cytoprotective signaling when activated by flavonoids and azoles.^1,31-33 Additionally, AhR regulates epithelial homeostasis, via immune-mediated skin responses and skin barrier effects.^1,34-36 AhR is widely expressed in skin cells, including keratinocytes, macrophages, dendritic cells, T-cell subtypes, Treg cells, mast cells, neutrophils, and resident memory T cells (TRM).^37,38 In immune cells, AhR signaling reduces the Th2 differentiation and cytokine expression implicated in AD, including IL-4, IL-5, and IL-13.^9,37,39 Furthermore, AhR signaling regulates the differentiation of CD4+ Th cells that produce inflammatory cytokines^1,37 and decreases major histocompatibility complex class II expression and the production of Th2- (IL-4, IL-5, and IL-13), Th1 and Th17- cytokines (IL-21 and IL-22).^40,41 

AhR signaling also regulates keratinocyte differentiation, promotes skin-barrier integrity, and prevents transdermal water loss.^35,42 To normalize skin-barrier integrity, AhR signaling upregulates barrier components including proteins such as filaggrin, loricrin, hornerin, and involucrin, as well as ceramide lipids.^22,24 AhR-mediated activation of the Nrf2 transcription factor induces cytoprotective antioxidant responses that suppress oxidative stress, which further promotes skin homeostasis.^24,43

AhR in Dermatologic Inflammatory Diseases

Alterations in AhR expression are known to occur in inflammatory skin diseases, including psoriasis and AD.^6,14 Targeting AhR in inflammatory skin diseases may therefore provide an innovative approach to alter multiple disease mechanisms via a single receptor, in contrast to therapeutic agents that inhibit specific cytokines or enzymes.^42,44,45 AD is multifactorial and heterogenous, thus modulation of multiple upstream mechanisms via AhR could be advantageous in restoring homeostasis to address underlying pathophysiologic processes (disease modification) in addition to improving symptoms. 

AD is a chronic relapsing-remitting disease affecting approximately 25% of children and 7–10% of adults worldwide. About 40% of adults and 33% of children with AD have moderate to severe disease.^46,47 Patients with AD are at high risk of developing other type 2 inflammatory diseases, food allergies, allergic rhinitis, and asthma. AD has an impact on sleep, and psychosocial functioning due to persistent pruritus and stigma associated with visibly affected skin.^12,18 

There is no curative therapy for AD and treatment aims to reduce inflammation, relieve core symptoms such as pruritus, and reduce the frequency and severity of flares to improve quality of life.¹⁸  Topical agents form the mainstay of treatment in patients with mild to moderate AD, with initial options including topical corticosteroids (TCSs) or topical phosphodiesterase-4 inhibitors; and topical calcineurin inhibitors or Janus kinase (JAK) inhibitors as second-line options.⁴⁸ With increasing severity, more potent TCSs may be used, however, concerns exist regarding application location, extent of body surface area treated, and long-term use, especially for mid- and high-potency TCSs.^49,50 Adverse events with TCSs, some of which are irreversible, include acne, rosacea, perioral dermatitis, facial erythema, hirsutism, skin thinning and atrophy, striae, telangiectasia, ecchymosis, dyschromia, and withdrawal phenomena.⁴⁹ Consequently, the use of TCSs is often limited or restricted, especially in sensitive skin regions (eg, face and skin flexures/intertriginous areas) and in infants and younger children who are at increased risk of systemic absorption and potential adverse events. Therefore, a need remains for efficacious non-steroidal topical therapies that can be used without these restrictions in patients down to 2 years of age.

The etiology of AD is multifactorial, involving epidermal barrier and immunologic dysfunction, genetics, and environmental factors (Figure 1).⁵¹ A healthy epidermal barrier protects against water loss, pathogens, and inflammatory stimuli. In AD, changes