Cytokine production in the skin is regulated by metabolites from the microbiome that influence histone acetylation.

Abstract

Abstract Immune functions of the skin, including cytokine production from epidermal keratinocytes, are influenced by the resident microbiota. We hypothesized that a prominent member of the normal skin microbiome, Propionibacterium acnes (P. acnes), can affect cutaneous inflammation through the epigenetic mechanism of inhibiting histone deacetylase (HDAC) activity. GC-MS analysis revealed that P. acnes can generate high levels of the short-chain fatty acids (SCFAs) propionic and valeric acid. These molecules increased levels of histone acetylation as seen by Western blot analysis of H3K9ac and H3K27ac and ChIP-PCR of H3K9ac in the IL-6 promoter. Using qPCR, RNA-sequencing, and multiplex ELISA we found that HDAC inhibition alone had no effect on cytokine production from primary cultures of normal human keratinocytes (NHEK), but greatly increased the production of many cytokines and chemokines (i.e. IL-1β, IL-6, IL-8, TNFα, and CCL5) elicited by ligands of TLR2 or TLR3. In direct contrast, HDAC inhibition suppressed TLR-mediated inductions of these cytokines in monocytes and dendritic cells. The mechanism of inhibition in PBMCs and DCs was consistent with previous findings demonstrating increased expression of Mi-2β and activation of the NuRD co-repressor complex, events that were absent in NHEK. Inhibition of HDAC activity in mouse skin confirmed these responses in vivo. siRNA screening identified a novel mechanism involving HDAC8 and HDAC9 as responsible for these effects in keratinocytes. Together, these results show that the skin local environment and microbe-derived SCFAs influence inflammatory gene expression in a cell type-specific manner, thus explaining selective inflammation in diseases such as acne.