Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas
Open accessAbstract
Significance: Tuberculosis (TB) granulomas represent sites of both bacterial containment and tissue pathology. Macrophage killing of Mycobacterium tuberculosis ( Mtb ) in granulomas to contain infection must be regulated to prevent collateral tissue damage. Nitric oxide synthase-2 (NOS2) and arginase-1 (Arg1), macrophage enzymes metabolizing l -arginine, play key roles in this process. NOS2 produces reactive nitrogen intermediates to kill Mtb , whereas Arg1 regulates NOS2 activity via substrate competition. Arg1 activity could predominate in hypoxic regions of granulomas where NOS2 activity likely is suboptimal. Here we show that Arg1 plays a central role in restricting bacterial growth and restraining tissue damage within granulomas in TB and other chronic inflammatory diseases. These findings point to the modulation of Arg1 activity as a potential host-directed therapy for TB.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the absence of functional NOS2, Arg1 exerts tissue protective effects and limits exacerbated granuloma formation and mycobacterial proliferation, traced to Arg1 controlling overwhelming T-cell activation.
“Recent evidence also suggests that in the absence of functional NOS2, Arg1 exerts tissue protective effects and limits exacerbated granuloma formation and mycobacterial proliferation, which could be traced back to the function of Arg1 in controlling overwhelming T-cell activation (109).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [109]
Cites
Mixed-Effects Models in Sand S-PLUS
Pinheiro, J. C., & Bates, D. M. (2000) · Statistics and Computing · doi:10.1007/978-1-4419-0318-1 · Cited by 11,187 · see citing works
nlme : Linear and nonlinear mixed effects models
DebRoy, S. (2006) · Medical Entomology and Zoology · Cited by 10,009 · see citing works
Mixed-Effects Models in S and S-PLUS
(2001) · Technometrics · doi:10.1198/tech.2001.s574 · Cited by 9,278 · see citing works
Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269 · see citing works
Self-citationNitric oxide and the immune response
Bogdan, C. (2001) · Nature Immunology · doi:10.1038/ni1001-907 · Cited by 3,447 · see citing works
Functional Polarization of Tumour-Associated Macrophages by Tumour-Derived Lactic Acid
Colegio, O. R., Chu, N.-Q., Szabo, A. L., Chu, T., Rhebergen, A. M., Jairam, V., Cyrus, N., Brokowski, C. E., Eisenbarth, S. C., Phillips, G. M., et al. (2014) · Nature · doi:10.1038/nature13490 · Cited by 3,046 · see citing works
Alternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745 · see citing works
Regulation of immune responses by L-arginine metabolism
Bronte, V., & Zanovello, P. (2005) · Nature Reviews Immunology · doi:10.1038/nri1668 · Cited by 1,775 · see citing works
Antimicrobial reactive oxygen and nitrogen species: concepts and controversies
Fang, F. C. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro1004 · Cited by 1,676 · see citing works
Identification of nitric oxide synthase as a protective locus against tuberculosis
MacMicking, J. D., North, R. J., LaCourse, R., Mudgett, J. S., Shah, S. K., & Nathan, C. F. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5243 · Cited by 1,180 · see citing works
Revisiting the role of the granuloma in tuberculosis
Ramakrishnan, L. (2012) · Nature reviews. Immunology · doi:10.1038/nri3211 · Cited by 887 · see citing works
Zea, A. H., Rodrı́guez, P. C., Atkins, M. B., Hernandez, C., Signoretti, S., Zabaleta, J., McDermott, D. F., Quiceno, D. G., Youmans, A. J., O’Neill, A., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4505 · Cited by 852 · see citing works
Foamy macrophages and the progression of the human tuberculosis granuloma
Russell, D. G., Cardona, P.-J., Kim, M., Allain‐Maillet, S., & Altare, F. (2009) · Nature Immunology · doi:10.1038/ni.1781 · Cited by 822 · see citing works
Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis
Pesce, J. T., Ramalingam, T. R., Mentink-Kane, M. M., Wilson, M. S., El Kasmi, K. C., Smith, A. M., Thompson, R. W., Cheever, A. W., Murray, P. J., & Wynn, T. A. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000371 · Cited by 816 · see citing works
Self-citationMeintjes, G., Lawn, S. D., Scano, F., Maartens, G., French, M. A., Worodria, W. O., Elliott, J., Murdoch, D. M., Wilkinson, R. J., Seyler, C., et al. (2008) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(08)70184-1 · Cited by 746 · see citing works
Rodrı́guez, P. C., & Ochoa, A. C. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00608.x · Cited by 722 · see citing works
Hesse, M., Modolell, M., Flamme, A. C. L., Schito, M. L., Fuentes, J. M., Cheever, A. W., Pearce, E. J., & Wynn, T. A. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.11.6533 · Cited by 706 · see citing works
El Kasmi, K. C., Qualls, J. E., Pesce, J. T., Smith, A. M., Thompson, R. W., Henao-Tamayo, M., Basaraba, R. J., König, T., Schleicher, U., Koo, M.-S., et al. (2008) · Nature Immunology · doi:10.1038/ni.1671 · Cited by 646 · see citing works
Self-citationWho puts the tubercle in tuberculosis?
Russell, D. G. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1538 · Cited by 641 · see citing works
Obstacles and opportunities for understanding macrophage polarization
Murray, P. J., & Wynn, T. A. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.0710409 · Cited by 558 · see citing works
Self-citationLin, P. L., Ford, C. B., Coleman, M. T., Myers, A. J., Gawande, R., Ioerger, T., Sacchettini, J., Fortune, S. M., & Flynn, J. L. (2014) · Nature Medicine · doi:10.1038/nm.3412 · Cited by 533 · see citing works
New insights into the function of granulomas in human tuberculosis
Ulrichs, T., & Kaufmann, S. H. E. (2006) · Journal of Pathology · doi:10.1002/path.1906 · Cited by 421 · see citing works
Self-citationMacrophages and control of granulomatous inflammation in tuberculosis
Flynn, J. L., Chan, J., & Lin, P. L. (2011) · Mucosal Immunology · doi:10.1038/mi.2011.14 · Cited by 415 · see citing works
Macrophage responses to hypoxia: relevance to disease mechanisms
Lewis, J. S., Lee, J. A., Underwood, J. C. E., Harris, A. L., & Lewis, C. E. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.6.889 · Cited by 383 · see citing works
Ulrichs, T., Kosmiadi, G., Trusov, V., Jörg, S., Pradl, L., Titukhina, M., Mishenko, V., Gushina, N., & Kaufmann, S. (2004) · Journal of Pathology · doi:10.1002/path.1628 · Cited by 348 · see citing works
Self-citationMycobacterium tuberculosis Growth at theCavity Surface: a Microenvironment with FailedImmunity
Kaplan, G., Post, F. A., Moreira, A. L., Wainwright, H., Kreiswirth, B. N., Tanverdi, M., Mathema, B., Ramaswamy, S. V., Walther, G., Steyn, L. M., et al. (2003) · Infection and Immunity · doi:10.1128/iai.71.12.7099-7108.2003 · Cited by 344 · see citing works
Mattila, J. T., Ojo, O. O., Kepka‐Lenhart, D., Marino, S., Kim, J. H., Eum, S. Y., Via, L. E., Barry, C. E., Klein, E. C., Kirschner, D. E., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300113 · Cited by 340 · see citing works
Control of immune response by amino acid metabolism
Grohmann, U., & Bronte, V. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00915.x · Cited by 311 · see citing works
Kropf, P., Fuentes, J. M., Fähnrich, E., Arpa, L., Herath, S., Weber, V., Soler, G., Celada, A., Modolell, M., & Müller, I. (2005) · The FASEB Journal · doi:10.1096/fj.04-3416fje · Cited by 297 · see citing works
Decreased Arginine Bioavailability and Increased Serum Arginase Activity in Asthma
Morris, C. R., Poljakovic, M., Lavrisha, L., Machado, L., Kuypers, F. A., & Morris, S. M. (2004) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200309-1304oc · Cited by 282 · see citing works
The mechanisms by which polyamines accelerate tumor spread
Soda, K. (2011) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-30-95 · Cited by 271 · see citing works
Kasmi, K. C. E., Pugliese, S. C., Riddle, S. R., Poth, J. M., Anderson, A. L., Frid, M. G., Li, M., Pullamsetti, S. S., Savai, R., Nagel, M. A., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303048 · Cited by 247 · see citing works
Role of arginine metabolism in immunity and immunopathology
Peranzoni, E., Marigo, I., Dolcetti, L., Ugel, S., Sonda, N., Taschin, E., Mantelli, B., Bronte, V., & Zanovello, P. (2007) · Immunobiology · doi:10.1016/j.imbio.2007.09.008 · Cited by 178 · see citing works
Dorhoi, A., Reece, S. T., & Kaufmann, S. H. E. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00994.x · Cited by 167 · see citing works
Self-citationGobert, A. P., Daulouède, S., Lepoivre, M., Boucher, J. L., Bouteille, B., Buguet, A., Cespuglio, R., Veyret, B., & Vincendeau, P. (2000) · Infection and Immunity · doi:10.1128/iai.68.8.4653-4657.2000 · Cited by 167 · see citing works
Qualls, J. E., Neale, G. A. M., Smith, A. M., Koo, M.-S., DeFreitas, A. A., Zhang, H., Kaplan, G., Watowich, S. S., & Murray, P. J. (2010) · Science Signaling · doi:10.1126/scisignal.2000955 · Cited by 167 · see citing works
Self-citationPolyamine metabolism in Leishmania: from arginine to trypanothione
Colotti, G., & Ilari, A. (2010) · Amino Acids · doi:10.1007/s00726-010-0630-3 · Cited by 165 · see citing works
Schreiber, T., Ehlers, S., Heitmann, L., Rausch, A., Mages, J., Murray, P. J., Lang, R., & Hölscher, C. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803567 · Cited by 161 · see citing works
Self-citationUlrichs, T., Kosmiadi, G., Jörg, S., Pradl, L., Titukhina, M., Mishenko, V., Gushina, N., & Kaufmann, S. (2005) · Journal of Infectious Diseases · doi:10.1086/430621 · Cited by 150 · see citing works
Self-citationLouis, C. A., Reichner, J. S., Henry, W. L., Mastrofrancesco, B., Gotoh, T., Mori, M., & Albina, J. E. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.274.3.r775 · Cited by 136 · see citing works
Tuberculosis Immunopathology: The Neglected Role of Extracellular Matrix Destruction
Elkington, P. T., D'Armiento, J. M., & Friedland, J. S. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3001847 · Cited by 127 · see citing works
The granulomatous inflammatory exudate.
Spector, W. G. (1969) · PubMed · Cited by 126 · see citing works
Arginase I Suppresses IL-12/IL-23p40–Driven Intestinal Inflammation during Acute Schistosomiasis
Herbert, D. R., Orekov, T., Roloson, A., Ilies, M., Perkins, C. L., O’Brien, W. E., Cederbaum, S. D., Christianson, D. W., Zimmermann, N., Rothenberg, M. E., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902009 · Cited by 125 · see citing works
The IL ‐13/ IL‐4R α axis is involved in tuberculosis‐associated pathology
Heitmann, L., Dar, M. A., Schreiber, T., Erdmann, H., Behrends, J., McKenzie, A. N. J., Brombacher, F., Ehlers, S., & Hölscher, C. (2014) · The Journal of Pathology · doi:10.1002/path.4399 · Cited by 124 · see citing works
Bieren, J. E., Mosconi, I., Guiet, R., Piersgilli, A., Volpe, B., Chen, F., Gause, W. C., Seitz, A., Verbeek, J. S., & Harris, N. L. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003771 · Cited by 112 · see citing works
Modolell, M., Choi, B., Ryan, R. O., Hancock, M., Titus, R. G., Abebe, T., Hailu, A., Müller, I., Rogers, M. E., Bangham, C. R. M., et al. (2009) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0000480 · Cited by 102 · see citing works
The Role of Nitric Oxide in Mycobacterial Infections
Yang, C., Yuk, J., & Jo, E. (2009) · Immune Network · doi:10.4110/in.2009.9.2.46 · Cited by 101 · see citing works
Penitentiary or penthouse condo: the tuberculous granuloma from the microbe's point of view
Paige, C., & Bishai, W. R. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01424.x · Cited by 95 · see citing works
Reece, S. T., Loddenkemper, C., Askew, D. J., Zedler, U., Schommer-Leitner, S., Stein, M., Mir, F. A., Dorhoi, A., Mollenkopf, H., Silverman, G. A., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42796 · Cited by 93 · see citing works
Self-citationStempin, C. C., Dulgerian, L. R., Garrido, V. V., & Cerbán, F. M. (2009) · BioMed Research International · doi:10.1155/2010/683485 · Cited by 86 · see citing works
Who Benefits from Granulomas, Mycobacteria or Host?
Bold, T. D., & Ernst, J. (2009) · Cell · doi:10.1016/j.cell.2008.12.032 · Cited by 85 · see citing works
Mouse Strain Susceptibility to Trypanosome Infection: An Arginase-Dependent Effect
Duleu, S., Vincendeau, P., Courtois, P., Semballa, S., Lagroye, I., Daulouède, S., Boucher, J., Wilson, K. T., Veyret, B., & Gobert, A. P. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.10.6298 · Cited by 84 · see citing works
Role of Arginase 1 from Myeloid Cells in Th2-Dominated Lung Inflammation
Barron, L., Smith, A. M., Kasmi, K. C. E., Qualls, J. E., Huang, X., Cheever, A. W., Borthwick, L. A., Wilson, M. S., Murray, P. J., & Wynn, T. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061961 · Cited by 84 · see citing works
Self-citationJung, Y., LaCourse, R., Ryan, L., & North, R. J. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20021186 · Cited by 79 · see citing works
Gr1intCD11b+ Myeloid-Derived Suppressor Cells in Mycobacterium tuberculosis Infection
Obregón-Henao, A., Henao-Tamayo, M., Orme, I. M., & Ordway, D. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080669 · Cited by 74 · see citing works
Local Increase of Arginase Activity in Lesions of Patients with Cutaneous Leishmaniasis in Ethiopia
Abebe, T., Hailu, A., Woldeyes, M., Mekonen, W., Bilcha, K. D., Cloke, T., Fry, L., al Basatena, N.-K. S., Corware, K., Modolell, M., et al. (2012) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0001684 · Cited by 67 · see citing works
Reece, S. T., & Kaufmann, S. H. E. (2011) · Current Opinion in Microbiology · doi:10.1016/j.mib.2011.10.006 · Cited by 62 · see citing works
Self-citationL-arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis
Ralph, A. P., Kelly, P. M., & Anstey, N. M. (2008) · Trends in Microbiology · doi:10.1016/j.tim.2008.04.003 · Cited by 62 · see citing works
Arginase-1 expression in granulomas of tuberculosis patients: Figure 1
Pessanha, A. P., Martins, R. A. P., Mattos‐Guaraldi, A. L., Vianna, A. R. D. C. B., & Moreira, L. O. (2012) · FEMS Immunology & Medical Microbiology · doi:10.1111/j.1574-695x.2012.01012.x · Cited by 56 · see citing works
Arrais-Silva, W. W., Paffaro, V. A., Yamada, A. T., & Giorgio, S. (2004) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2004.09.002 · Cited by 47 · see citing works
Tavares, J., Ouaissi, A., Lin, P. K. T., et al. (2005) · International Journal for Parasitology · doi:10.1016/j.ijpara.2005.01.008 · Cited by 42 · see citing works
Polyamine uptake by the intraerythrocytic malaria parasite, Plasmodium falciparum
Niemand, J., Louw, A. I., Birkholtz, L., et al. (2012) · International Journal for Parasitology · doi:10.1016/j.ijpara.2012.07.005 · Cited by 29 · see citing works
Araújo, A. P., Frezza, T. F., Allegretti, S. M., & Giorgio, S. (2010) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2010.09.003 · Cited by 28 · see citing works
Nathan, C. (2008) · Science · doi:10.1126/science.1167452 · Cited by 21 · see citing works
Differential Trafficking of TLR1 I602S Underlies Host Protection against Pathogenic Mycobacteria
Hart, B. E., & Tapping, R. I. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201545 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989 · see citing works
Nitric oxide synthase in innate and adaptive immunity: an update
Bogdan, C. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.01.003 · Cited by 862 · see citing works
DestVI identifies continuums of cell types in spatial transcriptomics data
Lopez, R., Li, B., Keren-Shaul, H., Boyeau, P., Kedmi, M., Pilzer, D., Jelinski, A., Yofe, I., David, E., Wagner, A., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01272-8 · Cited by 276 · see citing works
“This observation is also consistent with previous work, as cells with similar phenotypes have been observed to congregate in hypoxic tissue niches (cancerous [60] and non-cancerous [61]).”
ResultSchleicher, U., Paduch, K., Debus, A., Obermeyer, S., König, T., Kling, J. C., Ribechini, E., Dudziak, D., Mougiakakos, D., Murray, P. J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.001 · Cited by 136 · see citing works
Self-citation
- Authors
- Duque-Correa, M. A., Kühl, A. A., Rodriguez, P. C., Zedler, U., Schommer-Leitner, S., Rao, M., Weiner, J., Hurwitz, R., Qualls, J. E., Kosmiadi, G. A., Murray, P. J., Kaufmann, S. H. E., & Reece, S. T.
- Affiliations
- Department of Immunology and
- Charité – Universitätsmedizin Berlin (DE)
- Department of Microbiology, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112;
- Max Planck Society (DE)
- St. Jude Children's Research Hospital (US)
- Central Scientific Research Institute of Tuberculosis Russian Academy of Medical Sciences (RU)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-09-08
- Volume
- 111
- Issue
- 38
- Pages
- E4024-32
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4183271
- OpenAlex
- W2147041037
- Cited by
- 146
- References
- 65
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 15 · 2023: 6 · 2022: 3 · 2021: 14 · 2020: 14 · 2019: 12 · 2018: 9 · 2017: 11 · 2016: 13 · 2015: 17 · 2014: 5 · 2012: 1
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Cancer Institute (P 30CA 21765, P30CA021765)
- National Institute of Allergy and Infectious Diseases (R21AI097485, AI097485)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- arginase-1, nitric oxide synthase 2, Mycobacterium tuberculosis, tuberculosis granuloma, hypoxia, macrophages, arginine metabolism, substrate competition, T cell proliferation, bacterial load, nitric oxide
- MeSH terms
- Animals, Hypoxia, Arginase, Arginine, Disease Models, Animal, Granuloma, Humans, Lung, Macrophages, Mycobacterium tuberculosis, Nitric Oxide, T-Lymphocytes, Tuberculosis, Pulmonary, Mice, Knockout, Cell Proliferation, Mice, Nitric Oxide Synthase Type II
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
