Keith Wilson
Faculty Member
Last active: 12/19/2020

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

Hardbower DM, Asim M, Luis PB, Singh K, Barry DP, Yang C, Steeves MA, Cleveland JL, Schneider C, Piazuelo MB, Gobert AP, Wilson KT
Proc Natl Acad Sci U S A. 2017 114 (5): E751-E760

PMID: 28096401 · PMCID: PMC5293075 · DOI:10.1073/pnas.1614958114

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.

MeSH Terms (20)

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

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