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Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):E12091-E12100. doi: 10.1073/pnas.1814132115. Epub 2018 Nov 21.

Tissue-specific contributions of Tmem79 to atopic dermatitis and mast cell-mediated histaminergic itch.

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Department of Physiology, University of California, San Francisco, CA 94143.
School of Dentistry, University of California, San Francisco, CA 94143.
Department of Dermatology, University of California, San Francisco, CA 94143.
Vision Science Graduate Program, School of Optometry, University of California, Berkeley, CA 94720.
Department of Physiology, University of California, San Francisco, CA 94143;


Atopic dermatitis (AD) is the most common skin disease in children. It is characterized by relapsing inflammation, skin-barrier defects, and intractable itch. However, the pathophysiology of itch in AD remains enigmatic. Here, we examine the contribution of Tmem79, an orphan transmembrane protein linked to AD in both mice and humans. We show that Tmem79 is expressed by both keratinocytes and sensory neurons, but that loss of keratinocytic Tmem79 is sufficient to elicit robust scratching. Tmem79 -/- mice demonstrate an accumulation of dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In Tmem79 -/- mice, mast cell degranulation produces histaminergic itch in a histamine receptor 1/histamine receptor 4 (H4R/H1R)-dependent manner that may involve activation of TRPV1- afferents. TMEM79 has limited sequence homology to a family of microsomal glutathione transferases and confers protection from cellular accumulation of damaging reactive species, and may thus play a role in regulating oxidative stress. In any case, mechanistic insights from this model suggest that therapeutics targeting PGE2 and/or H1R/H4R histaminergic signaling pathways may represent useful avenues to treat Tmem79-associated AD itch. Our findings suggest that individuals with mutations in Tmem79 develop AD due to the loss of protection from oxidative stress.


Tmem79; atopic dermatitis; itch; oxidative stress; prostaglandin E2

[Available on 2019-06-18]

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