title: TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis.
abstract: 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.
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Oh
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Oh
authors.forename: Jingning
authors.initials: J
authors.lastname: Lu
authors.forename: Hongfei
authors.initials: H
authors.lastname: Lou
authors.forename: Allen C
authors.initials: AC
authors.lastname: Myers
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009412:Nerve Fibers / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D011537:Pruritus / Q000276:immunology* / Q000517:prevention & control; D011687:Purines / Q000008:administration & dosage; D000074025:TRPA1 Cation Channel; D058408:Th1-Th2 Balance; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D015220:Calcium Channels; D016207:Cytokines; D018793:Interleukin-13; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D011687:Purines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse