Inhibition of HDAC8 and HDAC9 by microbial short-chain fatty acids breaks immune tolerance of the epidermis to TLR ligands

Abstract

Epidermal keratinocytes participate in immune defense through their capacity to recognize danger, trigger inflammation, and resist infection. However, normal skin immune function must tolerate contact with an abundant community of commensal microbes without inflammation. We hypothesized that microbial environmental conditions dictate the production of molecules that influence epigenetic events and cause keratinocytes to break innate immune tolerance. , a commensal skin bacterium, produced the short-chain fatty acids (SCFAs) propionate and valerate when provided a lipid source in hypoxic growth conditions, and these SCFAs inhibited histone deacetylase (HDAC) activity. Inhibition of HDAC activity in keratinocytes promoted cytokine expression in response to Toll-like receptor (TLR) ligands for TLR2 or TLR3. This response was opposite to the action of HDAC inhibition on production of inflammatory cytokines by monocytes and involved HDAC8 and HDAC9 because small interfering RNA silencing of these HDACs recapitulated the activity of SCFAs. Analysis of cytokine expression in mice confirmed the response of the epidermis where application of SCFA on the skin surface promoted cytokine expression, whereas subcutaneous administration was inhibitory. These findings show that the products of commensal microbes made under specific conditions will inhibit HDAC activity and break tolerance of the epidermis to inflammatory stimuli.

Skin microbiota–host interactions

“…2). Some of these lipids, such as sapienic acid, can have antimicrobial activities 16 , while others, such as triglycerides, can be metabolized by microbes 17 into free fatty acids and di- and monoglycerides that can be bioactive against other microbes or stimulatory to host cells 18 .…”

Choreographing Immunity in the Skin Epithelial Barrier

“…Members of Corynebacterium species promote the expansion of IL-17-producing gd T cells through mycolic acid, a component of the cell envelope (Ridaura et al, 2018). In human skin, C. acnes produce short-chain fatty acids (SCFAs) in anaerobic conditions with a lipid substrate for fermentation, and SCFA-mediated histone deacetylase inhibition modulates inflammatory response of epidermal keratinocytes to TLR ligands (Sanford et al, 2016). Investigating how commensal-derived signals including bacterial elements and their metabolites prime skin immunity, and the precise receptor-ligand interactions involved, require further exploration.…”

Gut Microbiota, Immune System, and Bone

“…Butyrate regulates gene expression by inhibiting histone deacetylases (HDAC) [36], in particular butyrate inhibits HDAC1 and HDAC3 [37]. Also propionate acts as a less potent HDAC inhibitor [38]. Recently it has been suggested that inhibition of HADAC may increase Tregs development and function, hence this could be one of the mechanism by which GM enhances Treg generation in the gut [39].It has also been suggested that, depending on the cytokines milieu, interaction between SCFA and FFAR influences T cells differentiation not only towards Tregs, but also towards effector T cells.…”