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Ornithine Decarboxylase Regulates M1 Macrophage Activation And

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Ornithine Decarboxylase Regulates M1 Macrophage Activation And Ornithine decarboxylase regulates M1 macrophage PNAS PLUS activation and mucosal inflammation via histone modifications Dana M. Hardbowera,b, Mohammad Asimb, Paula B. Luisc, Kshipra Singhb, Daniel P. Barryb, Chunying Yangd,e, Meredith A. Steevese, John L. Clevelandd,e, Claus Schneiderc, M. Blanca Piazuelob, Alain P. Gobertb, and Keith T. Wilsona,b,f,g,h,1 aDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; bDivision of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; cDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232; dDepartment of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612; eDepartment of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458; fDepartment of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; gCenter for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN 37232; and hVeterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232 Edited by Carl F. Nathan, Weill Medical College of Cornell University, New York, NY, and approved December 20, 2016 (received for review September 6, 2016) Macrophage activation is a critical step in host responses during pathogens is macrophage activation. Macrophages have the ca- bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting pacity to alter cytokine/chemokine production and various other enzyme in polyamine metabolism, has been well studied in epithelial functions along the spectrum of M1 or M2 activation based on the cells and is known to have essential roles in many different cellular stimulus detected (12–14). M1 macrophages represent a highly functions. However, its role in regulating macrophage function during proinflammatory and antimicrobial subset of macrophages (12–14). bacterial infections is not well characterized. We demonstrate that M2 macrophages have various roles in wound repair, antiparasitic macrophage-derived ODC is a critical regulator of M1 macrophage responses, control of inflammation, and have been implicated in activation during both Helicobacter pylori and Citrobacter rodentium – tumor development and growth (15 18).TheroleofODChas INFLAMMATION infection. Myeloid-specific Odc deletion significantly increased gastric been well characterized in M2 macrophage responses to various IMMUNOLOGY AND and colonic inflammation, respectively, and enhanced M1 activation. parasitic and fungal infections (19–21), but the role of ODC in Add-back of putrescine, the product of ODC, reversed the increased macrophages during M1 responses has been less well studied (22). macrophage activation, indicating that ODC and putrescine are reg- We have demonstrated that ODC expression is up-regulated dur- ulators of macrophage function. Odc-deficient macrophages had ing bacterial infections (23–26), but the role in macrophage acti- increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 vation patterns requires further investigation. acetylation, accompanied by decreased H3K9 di/trimethylation both To address this question, we used Helicobacter pylori,aglobally in vivo and ex vivo in primary macrophages. These alterations in chro- pervasive human pathogen that represents the single greatest risk matin structure directly resulted in up-regulated gene transcription, factor in the development of gastric cancer (27–30). H. pylori es- especially M1 gene expression. Thus, ODC in macrophages tempers tablishes a chronic infection in humans, which can be recapitulated antimicrobial, M1 macrophage responses during bacterial infections in mice (14), marked by continuous, low-grade inflammation through histone modifications and altered euchromatin formation, and host tolerance of the pathogen (31–34).WealsousedtheCit- leading to the persistence and pathogenesis of these organisms. robacter rodentium infectious colitis model (26, 35). C. rodentium macrophage polarization | polyamines | histone modifications | Significance ornithine decarboxylase | Helicobacter pylori The pathogenesis of many bacteria is enhanced by the ability to olyamine metabolism is a process critical for life occurring establish persistent infection. Macrophages, particularly classically Pwithin all mammalian cell types (1, 2). Polyamines have ubiq- activated M1 macrophages, provide essential functions in the uitous roles in many cellular functions, including growth, pro- initiation of antibacterial immune responses. The regulation of liferation, and differentiation (1). Importantly, polyamines have macrophage activation is still poorly understood. Here, we dem- also been implicated in the alteration of histone modifications and onstrate that ornithine decarboxylase (ODC), the rate-limiting chromatin structure and thus might broadly affect DNA stability enzyme in polyamine synthesis, regulates M1 activation during and transcription (3–5). The production of the three major Helicobacter pylori Citrobacter rodentium — — and infection. Deletion polyamines putrescine, spermidine, and spermine is tightly of Odc in macrophages resulted in increased inflammation and regulated and centers on the rate-limiting enzyme, ornithine decreased bacterial persistence in mouse models. The enhanced decarboxylase (ODC1, hereafter referred to as ODC) (2, 6). M1 response was due to alterations in histone modifications, ODC uses the substrate, L-ornithine, to produce putrescine via a resulting in changes in chromatin structure and up-regulated decarboxylation reaction (2, 6). Given its essential and central transcription. These findings represent a novel mechanism by role in regulating polyamine metabolism within cells, ODC has which ODC directly regulates macrophage activation and pro- been highly studied and implicated in several malignancies, in- vides new insights into understanding bacterial persistence. cluding breast, colorectal, and gastric cancer (7–11). However, most of the studies related to ODC have been focused on its role Author contributions: D.M.H., A.P.G., and K.T.W. designed research; D.M.H., M.A., P.B.L., K.S., in epithelial cell function, leaving many questions surrounding C.S., and M.B.P. performed research; D.P.B., C.Y., M.A.S., and J.L.C. contributed new reagents/ the role of ODC in immune cells unanswered. analytic tools; D.M.H. and K.T.W. analyzed data; and D.M.H. and K.T.W. wrote the paper. In particular, macrophages are a significant component of The authors declare no conflict of interest. the innate immune cell compartment and play wide-ranging This article is a PNAS Direct Submission. roles in immune surveillance, responses to pathogens, wound 1To whom correspondence should be addressed. Email: [email protected]. healing, embryonic development, and regulation of the tumor This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. microenvironment (12, 13). An essential step in the responses to 1073/pnas.1614958114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1614958114 PNAS | Published online January 13, 2017 | E751–E760 Downloaded by guest on September 29, 2021 is an enteric bacterial pathogen that forms attaching and macrophage-derived ODC would have significant effects on effacing lesions in the colon and is similar to enteropathogenic H. pylori pathogenesis, specifically in the regulation of gastric in- Escherichia coli infection in humans (36). As macrophages are flammation. As H. pylori is a human pathogen, we first assessed known to have a critical role in H. pylori-mediated gastritis (14, 37) ODC levels in mononuclear cells in gastric biopsies from patients and C. rodentium colitis (14), we sought to interrogate the specific from Colombia infected with H. pylori with chronic active gastritis, role of ODC in macrophages during these enteric infections, using where overall risk of gastric cancer is high (39, 40). We found that a myeloid/macrophage-specific Odc knockout mouse. H. pylori infection leads to a significant increase in ODC levels in In this study, we have uncovered a mechanism by which ODC and mononuclear cells, which includes abundant expression in cells its product, putrescine, regulates macrophage activation and func- with the appearance of macrophages (Fig. 1 A and B). tion. We show that macrophage-derived ODC plays a critical role in To confirm that human macrophages express increased ODC the inhibition of M1 macrophage activation to promote persistence during H. pylori infection, we performed immunofluorescence of infection. This defect in M1 macrophage activation is directly staining for ODC and CD68, a macrophage marker, on a subset of regulated by polyamine production that modulates chromatin struc- the cases from Colombia. Control staining in which no primary ture, as determined by alterations in histone modification markers in anti-ODC antibody was used was performed to confirm the vitro and in vivo, which prevents proinflammatory gene transcription. specificity of the staining (SI Appendix,Fig.S1A). As expected, the + + number of CD68 macrophages was increased in the H. pylori Results cases compared with the normal cases (SI Appendix,Fig.S1B). + – Myeloid-Specific ODC Deletion Enhances Gastritis and Bacterial Killing Whereas there was no difference in the number of CD68 ODC + During H. pylori Infection. As we have previously demonstrated macrophages between normal and H. pylori cases (SI Appendix, that ODC plays a significant
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