Tissue-specific contributions of Tmem79 to atopic dermatitis and mast cell-mediated histaminergic itch
Joshua J. Emricka,b, Anubhav Mathurc, Jessica Weid, Elena O. Grachevaa,1, Karsten Gronertd, Michael D. Rosenblumc, and David Juliusa,2
aDepartment of Physiology, University of California, San Francisco, CA 94143; bSchool of Dentistry, University of California, San Francisco, CA 94143; cDepartment of Dermatology, University of California, San Francisco, CA 94143; and dVision Science Graduate Program, School of Optometry, University of California, Berkeley, CA 94720
Contributed by David Julius, October 22, 2018 (sent for review August 16, 2018; reviewed by Isaac M. Chiu and Xinzhong Dong)
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 pathophysiol- ogy 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 keratino- cytic Tmem79 is sufficient to elicit robust scratching. Tmem79−/− mice demonstrate an accumulation of dermal mast cells, which are dimin- ished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In Tmem79−/− mice, mast cell degranula- tion produces histaminergic itch in a histamine receptor 1/histamine receptor 4 (H4R/H1R)-dependent manner that may involve acti- vation of TRPV1− afferents. TMEM79 has limited sequence ho- mology to a family of microsomal glutathione transferases and confers protection from cellular accumulation of damaging re- active 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 mu- tations in Tmem79 develop AD due to the loss of protection from oxidative stress.
