495 The molecular mechanism for IL-4 down-regulation of loricrin expression in atopic dermatitis is through sequestration of the coactivator CBP in the Jak-Stat6 pathway

Abstract

Although the pathogenesis of atopic dermatitis (AD) is not entirely clear, AD has been associated with filaggrin loss-of-function mutations, Th2 cytokines, and colonization with the gram-positive cocci S. aureus that contribute to the skin barrier defect and disease severity. To mimic skin scratching in AD patients, we performed scalpel cuts on the backs of filaggrindeficient (ft/ft) and wt (Balb/c) mice. Unexpectedly, w21 days after the skin injury, ft/ft mice but not wt mice spontaneously developed an expanding area of inflammation at the site of skin injury with clinical alopecia, erythema, and scale, histologic acanthosis and grampositive cocci colonization in the stratum corneum, an inflammatory infiltrate of monocytes, eosinophils, mast cells and neutrophils, and increased protein levels of (e.g., IL-1b) and the Th2-related cytokines (e.g., IL-33 and IL-31). Interestingly, topical treatment with a potent corticosteroid ointment (clobetasol) resulted in a greater degree of skin inflammation, and histologic sections revealed a marked increase in abundance of gram-positive cocci throughout the stratum corneum and hair follicles. In contrast, topical treatment with an antibiotic ointment (Neosporin) resulted in resolution of clinical and histologic skin inflammation, decreased inflammatory infiltrate, and reduced levels of proinflammatory and Th2 cytokines. Taken together, these findings provide a new in vivo mouse model of spontaneous AD development to investigate the specific roles of filaggrin deficiency, skin injury, and bacterial skin colonization in the pathogenesis of AD.