Epidermal Mechanical Scratching-Induced ROS Exacerbates the Itch-Scratch Cycle via TRPA1 Activation on Mast Cells in Atopic Dermatitis.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by the itch-scratch cycle. Itching, induced by irritants or allergens that stimulate pruriceptive neurons, triggers uncontrollable mechanical scratching, leading to epidermal barrier disruption, immune response activation, inflammatory mediator release, and further stimulation of pruritus conduction. Although oxidative stress and immune cells can exacerbate this cycle, the correlation between mechanical scratching, epidermal oxidative stress, and dermal mast cell activation in AD remains unclear. Here, by examining clinical specimens of AD, establishing a three-dimensional co-culture system of HaCaT and LAD2 cells, and utilizing a mechanical scratching mouse model of AD, we found that reactive oxygen species produced by mechanically stimulated HaCaT can activate TRPA1 on mast cells presenting tryptase (TPS). Implementing a free radical scavenger and TRPA1 inhibitor can inhibit mast cell activation and type II inflammatory response, thereby alleviating itching and skin lesions in AD. These results indicate that active oxygen scavenging combined with TRPA1 inhibition can inhibit the itch-scratch cycle, which may present a potential approach for the treatment of AD.