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

Abstract

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 <i>Tmem79</i>, an orphan transmembrane protein linked to AD in both mice and humans. We show that <i>Tmem79</i> is expressed by both keratinocytes and sensory neurons, but that loss of keratinocytic <i>Tmem79</i> is sufficient to elicit robust scratching. <i>Tmem79</i>^<i>-/-</i> mice demonstrate an accumulation of dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In <i>Tmem79</i>^<i>-/-</i> 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 <i>Tmem79</i>-associated AD itch. Our findings suggest that individuals with mutations in <i>Tmem79</i> develop AD due to the loss of protection from oxidative stress.