678 Site-specific microarray evaluation of spontaneous dermatitis in flaky tail mice

Abstract

Flaky tail mice (FTM) with gene mutations to filaggrin and TMEM79 are known to spontaneously develop atopic dermatitis (AD)-like dermatitis. Interestingly, we have already reported that the spontaneous development of dermatitis exhibits site-specificity, i.e., the face and neck develop spontaneous dermatitis, while the dorsal flank shows normal skin in old FTM. In fact, TEWL and SC pH increased, SC hydration decreased, and epidermis thickened in the neck, but not in the dorsal flank. The detailed pathogenic mechanisms of such site-specific emergence of dermatitis in AD remain unclear. To clarify the pathogenesis of site-specificity, we analyzed skin of the neck and dorsal flank in old FTM using a microarray. Many genes for keratin and keratin-associated protein were up-regulated in the neck compared with the dorsal flank. Several genes thought to be associated with the pathogenesis of AD, such as IL-4, 5, and 13, TSLP, TARC, loricrin, involucrin, transglutaminase 1, TMEM79, defensin, cathelicidin antimicrobial peptide, claudin 1, and EGFR, showed no significant changes between the neck and dorsal flank. In other AD-associated genes, filaggrin was up-regulated in the neck, and some members of the kallikrein and serine peptidase inhibitor family fluctuated. KEGG pathway analysis with DAVID ver. 6.8 revealed the most significant difference in the pathway of S. aureus infection between both sites (P<0.0001). In addition, multiple genes downstream of the peroxisome proliferator-activated receptor (PPAR) signaling pathway were down-regulated (P=0.0039), in line with our previous studies showing therapeutic effects of some PPAR activators in a hapten-induced murine AD model. Although further studies are necessary, the present findings suggest several candidates as genes associated with site-specific emergence of dermatitis in AD, including ones associated with S. aureus infection or PPARs.