MicroRNA-203 ameliorates skin inflammation in atopic dermatitis by suppressing mast cell hyperactivation via upregulating aryl hydrocarbon receptor signaling

Introduction: Atopic dermatitis (AD) is a chronic type-2-dominant inflammatory skin disease in which mast cells (MCs) amplify cutaneous inflammation. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates barrier and immune homeostasis, but the role of MC-intrinsic AhR and its upstream regulators in AD is poorly defined. Objectives: To define whether AhR controls MC effector function in AD, to identify upstream regulators of MC AhR, and to test whether topical AhR modulation alters allergen-driven cutaneous inflammation. Methods: We integrated human AD lesional biopsies and plasma analyses with a clinically relevant cockroach allergen (CRE)–induced AD-like mouse model (including mast cell–deficient KitW-sh and AhR-knockout mice), topical treatment with the AhR ligand benvitimod, and mechanistic in vitro studies in human LAD2 cells and murine bone marrow–derived mast cells (BMMCs) using small interfering RNA (siRNA), miR-203 mimics, luciferase reporters and functional readouts (degranulation, cytokine release, α-CaMKII signaling). Results: MC density and MC-intrinsic AhR expression were elevated in human AD lesions and in CRE-challenged skin. Genetic or siRNA-mediated loss of AhR enhanced allergen-induced MC degranulation and selectively increased epithelial alarmins (TSLP, IL-33) and systemic CRE-specific IgE/IgG1 in vivo. Topical benvitimod attenuated CRE-induced skin inflammation, MC accumulation/degranulation, and selected alarmins. Bioinformatic and experimental analyses identified skin-enriched miR-203 as upregulated in AD lesions and plasma; miR-203 unexpectedly promoted an AhR transcriptional program in MCs and suppressed allergen-induced degranulation via an AhR–α-CaMKII axis, an effect partially reversed by AhR knockdown. Conclusion: A conserved miR-203–AhR–α-CaMKII signaling axis restrains MC hyperactivation and mitigates allergen-driven type-2 skin inflammation. These findings reveal MC-intrinsic AhR as a regulatory brake in AD and support topical AhR modulation and miR-203–AhR pathway components as candidate therapeutic or biomarker targets for MC-high AD endotypes.