183 Reduced FLG expression in atopic eczema reduces expression of key barrier genes and increases BMP signalling

Filaggrin (FLG) is a key cornified envelope and epidermal barrier protein. FLG mutations are the most strongly implicated genetic risk factor for atopic eczema (AE). part of gene complex, called differentiation complex (EDC), genes which contribute to various aspects function. siRNA knockdown in keratinocytes caused global reduction EDC Keratin (KRT) expression concomitant with up-regulation bone morphogenetic protein (BMP) signalling. We confirmed this effect using qPCR panel KRT cover slip staining phospho-SMAD (pSMAD) 1/5/9, marker active BMP signaling. This led us hypothesise that signalling important AE pathogenesis. Microarray datasets from patients showed positive correlations between expression. Tape strips (TS) taken significant negative correlation pSMAD 1/5/9 expression, increased compound heterozygote patients. Skin biopsies an BMP2, BMP6, pSMAD1/5/9, downstream target signalling, ID1. Keratinocytes cultured BMP2 or BMP6 expressed more FLG, KRT1 Loricrin while treated receptor antagonist DMH1 had reduced Together these data suggest BMP-SMAD low may represent protective response chronic disruption. targetting can restore function AE.