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

E2BRN012 - Reduced FLG expression in atopic eczema reduces expression of key barrier genes and increases BMP signalling

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.