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

James A Sanford; Ling-Juan Zhang; Michael R Williams; Jon A Gangoiti; Chun-Ming Huang; Richard L Gallo

doi:10.1126/sciimmunol.aah4609

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

Sci Immunol. 2016 Oct 28;1(4):eaah4609. doi: 10.1126/sciimmunol.aah4609.

Authors

James A Sanford¹, Ling-Juan Zhang¹, Michael R Williams¹, Jon A Gangoiti², Chun-Ming Huang¹, Richard L Gallo³

Affiliations

¹ Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
² Biochemical Genetics and Metabolomics Laboratory, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
³ Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA. rgallo@ucsd.edu.

PMID: 28783689
DOI: 10.1126/sciimmunol.aah4609

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. Propionibacterium acnes, 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.