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

Microbial short-chain fatty acids inhibit HDAC activity and contribute to keratinocyte-triggered skin inflammation. Microbial fatty acids get under your skin 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.

[1]  P. Brigidi,et al.  The effect of short-chain fatty acids on human monocyte-derived dendritic cells , 2015, Scientific Reports.

[2]  M. Plikus,et al.  Dermal adipocytes protect against invasive Staphylococcus aureus skin infection , 2015, Science.

[3]  C. Lowenstein,et al.  Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen‐activated protein kinase phosphatase‐1 , 2014, Journal of leukocyte biology.

[4]  Huidong Shi,et al.  Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. , 2014, Immunity.

[5]  R. Medzhitov,et al.  The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition , 2014, Proceedings of the National Academy of Sciences.

[6]  F. Bushman,et al.  Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis , 2013, Nature.

[7]  Joanne L. Selway,et al.  Toll-like receptor 2 activation and comedogenesis: implications for the pathogenesis of acne , 2013, BMC Dermatology.

[8]  M. Yanagisawa,et al.  Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. , 2013, Gastroenterology.

[9]  Chun-Ming Huang,et al.  Fermentation of Propionibacterium acnes, a Commensal Bacterium in the Human Skin Microbiome, as Skin Probiotics against Methicillin-Resistant Staphylococcus aureus , 2013, PloS one.

[10]  Karsten Zengler,et al.  The microbiome extends to subepidermal compartments of normal skin , 2012, Nature Communications.

[11]  M. Garcia-Conesa,et al.  Alternative method for gas chromatography-mass spectrometry analysis of short-chain fatty acids in faecal samples. , 2012, Journal of separation science.

[12]  G. Natoli,et al.  Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages , 2012, Proceedings of the National Academy of Sciences.

[13]  Michal R. Gdula,et al.  Epigenetic Regulation of Gene Expression in Keratinocytes , 2012, The Journal of investigative dermatology.

[14]  Liping Zhao,et al.  Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers , 2011, The ISME Journal.

[15]  P. François,et al.  Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection. , 2011, Blood.

[16]  J. Epstein,et al.  Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells. , 2010, Developmental cell.

[17]  Paul A. Khavari,et al.  DNMT1 Maintains Progenitor Function in Self-Renewing Somatic Tissue , 2010, Nature.

[18]  Richard M Myers,et al.  Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. , 2009, Genome research.

[19]  R. Xavier,et al.  Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 , 2009, Nature.

[20]  J. Denu,et al.  Binding of the CHD4 PHD2 finger to histone H3 is modulated by covalent modifications. , 2009, The Biochemical journal.

[21]  Frank O. Nestle,et al.  Skin immune sentinels in health and disease , 2009, Nature Reviews Immunology.

[22]  Y. Obara,et al.  Short-chain fatty acid signaling pathways in bovine mammary epithelial cells , 2009, Regulatory Peptides.

[23]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[24]  D. Schrenk,et al.  Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. , 2008, The Journal of nutritional biochemistry.

[25]  Howard Y. Chang,et al.  Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. , 2008, Genes & development.

[26]  C. Lowenstein,et al.  Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling , 2008, The Journal of experimental medicine.

[27]  M. Usami,et al.  Butyrate and trichostatin A attenuate nuclear factor kappaB activation and tumor necrosis factor alpha secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells. , 2008, Nutrition research.

[28]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[29]  K. Schroder,et al.  Histone deacetylase inhibitors decrease Toll‐like receptor‐mediated activation of proinflammatory gene expression by impairing transcription factor recruitment , 2007, Immunology.

[30]  N. Pace,et al.  Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases , 2007, Proceedings of the National Academy of Sciences.

[31]  S. Smale,et al.  Selective and antagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response. , 2006, Genes & development.

[32]  B. Dréno,et al.  Induction of toll‐like receptors by Propionibacterium acnes , 2005, The British journal of dermatology.

[33]  Jenny Kim.  Review of the Innate Immune Response in Acne vulgaris: Activation of Toll-Like Receptor 2 in Acne Triggers Inflammatory Cytokine Responses , 2005, Dermatology.

[34]  J. Davie.  Inhibition of histone deacetylase activity by butyrate. , 2003, The Journal of nutrition.

[35]  S. Dowell,et al.  The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids* , 2003, The Journal of Biological Chemistry.

[36]  B. Hinnebusch,et al.  The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. , 2002, The Journal of nutrition.

[37]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[38]  W. Hörl,et al.  Anti‐inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL‐12 and up‐regulation of IL‐10 production , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  J. Leyden,et al.  Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne , 1995, Infection and immunity.

[40]  J. Cove,et al.  Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris. , 1992, The Journal of investigative dermatology.

[41]  R. Chalkley,et al.  The effect of sodium butyrate on histone modification , 1978, Cell.