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

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Title:	Inhibition of HDAC8 and HDAC9 by microbial short-chain fatty acids breaks immune tolerance of the epidermis to TLR ligands
Authors:	黃俊銘;Sanford, James A.;Zhang, Ling-Juan;Williams, Michael R.;Gangoiti, Jon A.;Huang, Chun-Ming;Gallo, Richard L.
Contributors:	生醫理工學院生醫科學與工程學系
Date:	2016-01-01
Issue Date:	2026-04-23 11:16:29 (UTC+8)
Publisher:	American Association for the Advancement of Science;United States: American Association for the Advancement of Science (AAAS)
Abstract:	摘要： Microbial short-chain fatty acids inhibit HDAC activity and contribute to keratinocyte-triggered skin inflammation. The skin plays host to many different species of microbes, tolerating their presence without the inflammatory response that greets more dangerous pathogens. Now, Sanford et al . report that short-chain fatty acids (SCFAs) produced by skin bacterium can lead to inflammatory response from keratinocytes. SCFAs produced by Propionibacterium acnes inhibited histone deacetylase (HDAC) activity in keratinocytes, which promoted the inflammatory response to innate immune ligands. These responses are cell-specific and environmentally specific—in a mouse model, SCFA induced cytokine expression on the skin but inhibited cytokine expression subcutaneously. Thus, microbial products may regulate immune tolerance of commensals in the skin. 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. 其他題名： Sci Immunol 出版者： United States: American Association for the Advancement of Science (AAAS) 出版日期： 2016-10-28 出處： Science Immunology, 2016-10, Vol.1 (4) 版權： Copyright © 2016, American Association for the Advancement of Science. 識別號： ISSN: 2470-9468 識別號： EISSN: 2470-9468 識別號： DOI: 10.1126/sciimmunol.aah4609 識別號： PMID: 28783689
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