Tissue-specific contributions of Tmem79 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 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.

Molecular Signature of Pruriceptive MrgprA3+ Neurons

“…Previous studies have shown an increased level of prostaglandin E2, an agonist for EP4, in the skin of patients with atopic dermatitis (Fogh et al, 1989). Consistently, blockade of PGE2 signaling reduced spontaneous scratching behavior in a mouse model of dermatitis (Emrick et al, 2018). Our analysis suggests that PGE2 might activate MrgprA3 þ neurons via the activation of EP4.…”

Natural Autoantibodies in Chronic Pulmonary Diseases

“…LOXL2 [42,43], LIMS1 [44], NINJ2 [41], HVCN1 [45,46], TMEM79 [47], VSTM2A [48], FNDC4 [49] Interestingly, especially among antigens recognized by INSIP patient sera, there are many extracellular or membrane proteins, which are accessible by antibodies even under normal conditions. This suggests that the antigen-antibody interactions may be implicated in the pathogenesis or clinical course of disease.…”

“…In addition to these three proteins, we identified other extracellular or membrane proteins including transmembrane protein 254 (TMEM254), prokineticin 1 (PROK1) [39], and CGRP receptor component (CRCP) [40], as targets of IPF natural autoantibodies. We also identified extracellular or membrane proteins including NINJ2 [41], transmembrane protein 79 (TMEM79) [47], V-Set and transmembrane domain containing 2A (VSTM2A) [48], and fibronectin type III domain containing 4 (FNDC4) [49], as targets of INSIP natural autoantibodies (Table 1).…”

Protective effect of linoleic acid against inflammatory reactions by mast cell via caspase‐1 cascade pathways

“…The bacteria Staphylococcus aureus is also extremely prevalent on the skin of patients with AD and accelerates AD (Weidinger & Novak, ). The canonical pathology of AD is often accompanied by an infiltrate of inflammatory cells (e.g., mast cells, eosinophils, and T lymphocytes) into the dermal layer of skin (Emrick et al, ). Infiltrated mast cells release the inflammatory mediators with many biological effects to regulate allergic inflammatory reaction by degranulation (Nam et al, ).…”