Molecular link between itch and atopic dermatitis

Abstract

Atopic dermatitis (AD) is a relapsing inflammatory skin disease often associated with intractable chronic itch. The sensation of itch depends on the activity of pruriceptive sensory neurons whose nerve fibers innervate the dermis and epidermis. These fibers can respond to factors secreted by keratinocytes (e.g., thymic stromal lymphopoietin) and immune cells (e.g., IL-31, histamine, and proteases) (1). However, the pathogenesis of chronic itch and inflammation in AD is not well understood, and therapeutic options are limited. In PNAS, Emrick et al. (2) perform an elegant study in which they determine the cellular and molecular mechanisms by which the AD-associated gene Tmem79 drives skin inflammation and itch. Emrick et al. find that TMEM79 acts as a putative glutathione transferase to decrease oxidative stress in keratinocytes to prevent mast cell activation and histamine-driven neuronal activation and itch (Fig. 1). This study is an important advance in our understanding of the molecular and cellular mechanisms of AD. Fig. 1. Tmem79 reduces oxidative stress to protect against itch and AD. Tmem79 , a gene linked to AD, is expressed in keratinocytes and sensory neurons. Emrick et al. (2) find that loss of Tmem79 causes an increase in RS in keratinocytes and the induction of PGE2 levels. PGE2 acts through EP3 receptors to recruit dermal mast cells. Mast cell degranulation results in the release of histamine, which acts on H1R and H4R expressed by C-fiber sensory neurons to drive itch. Potential strategies to inhibit itch in AD suggested by this study include the use of antioxidants, EP3 receptor antagonists, and histamine receptor (H4R/H1R) antagonists. AD affects ∼20% of children in the developed world and 2 to 8% of adults, with 87 to 100% of these patients experiencing chronic itch (3, 4). It is generally thought that AD is caused by a combination of skin … [↵][1]1To whom correspondence should be addressed. Email: isaac_chiu{at}hms.harvard.edu. [1]: #xref-corresp-1-1