title: Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications.
abstract: Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Hardbower
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Luis
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Kshipra
authors.initials: K
authors.lastname: Singh
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Barry
authors.affiliation: Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612.|Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Steeves
authors.affiliation: Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612.|Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Claus
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Alain P
authors.initials: AP
authors.lastname: Gobert
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; keith.wilson@vanderbilt.edu.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.|Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN 37232.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002460:Cell Line; D044082:Citrobacter rodentium; D003092:Colitis / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000276:immunology* / Q000473:pathology; D005753:Gastric Mucosa / Q000276:immunology / Q000473:pathology; D005756:Gastritis / Q000276:immunology / Q000473:pathology; D016481:Helicobacter Infections / Q000276:immunology* / Q000473:pathology; D016480:Helicobacter pylori; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000276:immunology*; D011700:Putrescine / Q000378:metabolism
chemical_list: D016207:Cytokines; D006657:Histones; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009955:Ornithine Decarboxylase; D011700:Putrescine
keywords: Helicobacter pylori; histone modifications; macrophage polarization; ornithine decarboxylase; polyamines