Targeting Of Hdac8 And Hdac9 In Keratinocytes To Enhance Skin Immune Defense

We recently reported that short-chain fatty acids (SCFA) promote an inflammatory response in keratinocytes by suppression of HDAC8 or HDAC9, specific histone deacetylases whose activity increases tolerance of the skin to inflammatory signals. Upon silencing of HDAC8 or 9 in keratinocytes, subsequent exposure to TLR2/6, TLR3, or TLR7 ligands enhances inflammatory cytokine production in keratinocytes, but this effect does not occur in bone-marrow derived cells, thus demonstrating epidermal specificity of this mechanism. Chip-Seq and signal pathway analysis by RNA-Seq identified MAP2K3 as a key intermediate in this process, with increased acetylation at H3K9 and H3K27 in the MAP2K3 promoter after silencing HDAC8 and HDAC9 or inhibition of HDAC activity by SCFA butyrate. Antibody pull-down and mass spec analysis showed that HDAC8 and HDAC9 bind the FACT complex to drive gene elongation. These responses were ablated with MAP2K3 knock down. Furthermore, HDAC8 and HDAC9 silencing in keratinocytes lead to IFN-β-dependent activation of antigen presentation ability in cultured dendritic cells and enhanced T cell proliferation in culture. Increased immune reactivity of keratinocytes was also seen in K14Cre-HDAC8/9flox mice in response to UV radiation or imiquimod application, thus validating the critical role of this epigenetic mechanism in the skin. To exploit a potential benefit of HDAC8 and HDAC9 inhibition, we evaluated the impact of HDAC inhibition by topical application of SCFAs on survival of S. aureus. Topical treatment of mice with butyrate upregulated antimicrobial peptide production (Camp and mBD4) and subsequently inhibited S. aureus in mice despite elevated Th2 cytokines generated in an MC903-induced AD mouse model. These observations show a novel approach to enhance host defense against pathogens on human skin.