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

Significance The pathogenesis of many bacteria is enhanced by the ability to establish persistent infection. Macrophages, particularly classically activated M1 macrophages, provide essential functions in the initiation of antibacterial immune responses. The regulation of macrophage activation is still poorly understood. Here, we demonstrate that ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, regulates M1 activation during Helicobacter pylori and Citrobacter rodentium infection. Deletion of Odc in macrophages resulted in increased inflammation and decreased bacterial persistence in mouse models. The enhanced M1 response was due to alterations in histone modifications, resulting in changes in chromatin structure and up-regulated transcription. These findings represent a novel mechanism by which ODC directly regulates macrophage activation and provides new insights into understanding bacterial persistence. 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.