title: Histone deacetylase inhibition enhances antimicrobial peptide but not inflammatory cytokine expression upon bacterial challenge.
abstract: Antimicrobial peptides (AMP) are defense effectors of the innate immunity playing a crucial role in the intestinal homeostasis with commensals and protection against pathogens. Herein we aimed to investigate AMP gene regulation by deciphering specific characteristics allowing their enhanced expression among innate immune genes, particularly those encoding proinflammatory mediators. Our emphasis was on epigenetic regulation of the gene encoding the AMP β-defensin 2 (HBD2), taken as a model of possibly specific induction, upon challenge with a commensal bacterium, compared with the proinflammatory cytokine IL-8. Using an in vitro model of colonic epithelial cells challenged with Escherichia coli K12, we showed that inhibition of histone deacetylases (HDAC) by trichostatin A dramatically enhanced induction of HBD2 expression, without affecting expression of IL-8. This mechanism was supported by an increased phosphorylation of histone H3 on serine S10, preferentially at the HBD2 promoter. This process occurred through activation of the IκB kinase complex, which also led to activation of NF-κB. Moreover, we demonstrated that NF-κB was modified by acetylation upon HDAC inhibition, partly by the histone acetyltransferase p300, and that both NF-κB and p300 supported enhanced induction of HBD2 expression. Furthermore, we identified additional genes belonging to antimicrobial defense and epithelial restitution pathways that showed a similar pattern of epigenetic control. Finally, we confirmed our finding in human colonic primary cells using an ex vivo organoid model. This work opens the way to use epigenetic pharmacology to achieve induction of epithelial antimicrobial defenses, while limiting the deleterious risk of an inflammatory response.
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75015 Paris, France; INSERM U1202, Institut Pasteur, 75015 Paris, France;
authors.forename: Natalie
authors.initials: N
authors.lastname: Fischer
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75015 Paris, France; INSERM U1202, Institut Pasteur, 75015 Paris, France;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sechet
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75015 Paris, France; INSERM U1202, Institut Pasteur, 75015 Paris, France;
authors.forename: Robin
authors.initials: R
authors.lastname: Friedman
authors.affiliation: Département de Gastroentérologie, Hôpital Henri Mondor, AP-HP, 94000 Créteil, France;
authors.forename: Aurélien
authors.initials: A
authors.lastname: Amiot
authors.affiliation: Département de Gastroentérologie, Hôpital Henri Mondor, AP-HP, 94000 Créteil, France;
authors.forename: Iradj
authors.initials: I
authors.lastname: Sobhani
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75015 Paris, France; INSERM U1202, Institut Pasteur, 75015 Paris, France;
authors.forename: Giulia
authors.initials: G
authors.lastname: Nigro
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75015 Paris, France; INSERM U1202, Institut Pasteur, 75015 Paris, France; Chaire de Microbiologie et Maladies Infectieuses, Collège de France, 75005 Paris, France philippe.sansonetti@pasteur.fr brice.sperandio@pasteur.fr.
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75015 Paris, France; INSERM U1202, Institut Pasteur, 75015 Paris, France; philippe.sansonetti@pasteur.fr brice.sperandio@pasteur.fr.
authors.forename: Brice
authors.initials: B
authors.lastname: Sperandio
mesh_terms: D018938:Caco-2 Cells; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000276:immunology; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000276:immunology; D048168:Escherichia coli K12 / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D023083:beta-Defensins / Q000276:immunology*
chemical_list: C508606:CXCL8 protein, human; C106641:DEFB4A protein, human; D056572:Histone Deacetylase Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D023083:beta-Defensins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: acetylation; antimicrobial peptides; colonic mucosa; epigenetic; epithelial cells