Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications

Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E751-E760. doi: 10.1073/pnas.1614958114. Epub 2017 Jan 17.


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.

Keywords: Helicobacter pylori; histone modifications; macrophage polarization; ornithine decarboxylase; polyamines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Citrobacter rodentium
  • Colitis / immunology
  • Colitis / pathology
  • Colon / immunology
  • Colon / pathology
  • Cytokines / immunology
  • Enterobacteriaceae Infections / immunology*
  • Enterobacteriaceae Infections / pathology
  • Gastric Mucosa / immunology
  • Gastric Mucosa / pathology
  • Gastritis / immunology
  • Gastritis / pathology
  • Helicobacter Infections / immunology*
  • Helicobacter Infections / pathology
  • Helicobacter pylori
  • Histones / metabolism*
  • Humans
  • Macrophage Activation
  • Macrophages / immunology*
  • Male
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Ornithine Decarboxylase / genetics
  • Ornithine Decarboxylase / immunology*
  • Putrescine / metabolism


  • Cytokines
  • Histones
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Ornithine Decarboxylase
  • Putrescine