hc-030031 and Dermatitis--Atopic

The aim of this study was to investigate the role of TRPA1 in the pathogenesis of AD.. The experimental atopic dermatitis (AD)-like skin lesions were established using 2,4-dinitrochlorobenzene (DNCB). Mice were divided into three groups: TRPA1. Lower dermatitis score, ear thickness, pruritus score, and epidermal hyperplasia were observed in mice in TRPA1. TRPA1 has a crucial role during the AD pathogenesis in mice, thus may be used as a potential new target for treating patients with chronic skin inflammatory disease.

Topics: Acetanilides; Animals; Dermatitis, Atopic; Dinitrochlorobenzene; Inflammation; Macrophages; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Pruritus; Purines; TRPA1 Cation Channel

Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In this study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13-transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1(+) dermal afferent nerves and TRPA1(+) mast cells in a Th2-dominated inflammatory environment.

Topics: Acetanilides; Animals; Calcium Channels; Cells, Cultured; Chronic Disease; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Humans; Interleukin-13; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Fibers; Nerve Tissue Proteins; Neuropeptides; Pruritus; Purines; Th1-Th2 Balance; Transient Receptor Potential Channels; TRPA1 Cation Channel; Up-Regulation