UCSF

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, a putative Membrane Associated Protein in Eicosanoid and Glutathione metabolism (MAPEG), to AD. We show that Tmem79 is expressed by both keratinocytes and sensory neurons and that loss of Tmem79 in both cell types contributes to development of the scratching phenotype observed in Tmem79 null mice. Interestingly, we find that loss of neuronal and keratinocytic Tmem79 contribute to scratching, but loss of keratinocytic Tmem79 alone is sufficient to elicit robust scratching. Tmem79 null mice accumulate dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In Tmem79 null mice, mast cell degranulation produces histaminergic itch in a H4R/H1R histamine receptor-dependent manner that may involve activation of TRPV1-negative afferents. Furthermore, acute antagonism of TRPA1, but not TRPV1, diminishes scratching, although compensatory mechanisms exist. Mechanistic insights from this model suggest that therapeutics targeting PGE2, H1R/H4R, or TRPA1 signaling pathways may represent useful avenues to treat Tmem79 null-associated AD itch.