ZAG Regulates the Skin Barrier and Immunity in Atopic Dermatitis

Adipokines modulate immune responses and lipid metabolism in allergic disease; however, little is known about their role in the skin barrier and atopic dermatitis (AD). We identified ZAG, an adipokine that regulates lipid mobilization, as a biomarker for AD. ZAG levels were consistently decreased in sera, T cells, and skin in human AD patients compared with healthy controls. ZAG was primarily detected in the stratum corneum along with FLG and LOR. Knockdown of ZAG with short hairpin RNA resulted in decreased FLG and increased TSLP. Topical ZAG treatment in AD mice recovered ZAG expression in the skin and improved AD-like symptoms, transepidermal water loss, and ceramide levels. Furthermore, topical ZAG treatment induced immunoregulatory effects, including reduction of IL-4, IL-17, and IFN-gamma and increased Foxp3 in the skin and lymphoid organs. Interestingly, ZAG treatment also recovered decreased levels of ADAM17, an important player in skin barrier function and immune response in AD. Thus, ZAG deficiency is closely related to skin barrier function and the immune abnormalities of AD, and we suggest that restoration of ZAG may be a promising therapeutic option for the treatment of AD.