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Toll-like receptor–induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens
Open accessAbstract
Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a 'loophole' in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 responses in which Arg1 expression is greatly increased by interleukin 4 and 13 signaling through the transcription factor STAT6, TLR-mediated Arg1 induction was independent of the STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.
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“Consequently, mice deficient in Arg1 are better protected against M. tuberculosis infection (108).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [108]
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“In contrast, arginase-1, which depletes the Nos2 substrate arginine by converting it to ornithine [62, 205], is reduced by heme.”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [62]
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Citations
Cites
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · cited 1×
“Although macrophage Arg1 expression is commonly linked to the hypothesized antiworm functions of alternatively activated macrophages (AAMs”
BackgroundNitric oxide and the immune response
Bogdan, C. (2001) · Nature Immunology · doi:10.1038/ni1001-907 · Cited by 3,447
Self-citationRecognition of microorganisms and activation of the immune response
Medzhitov, R. (2007) · Nature · doi:10.1038/nature06246 · Cited by 2,862 · cited 1×
“1671" language="eng" relation="no"> In macrophages, Toll-like receptors (TLRs) activate protective immune responses, including recognition of pathogens, activation of antipathogen effector pathways and transition to protective adaptive response”
BackgroundRegulation of immune responses by L-arginine metabolism
Bronte, V., & Zanovello, P. (2005) · Nature Reviews Immunology · doi:10.1038/nri1668 · Cited by 1,775 · cited 1×
“Although macrophage Arg1 expression is commonly linked to the hypothesized antiworm functions of alternatively activated macrophages (AAMs”
BackgroundFibrotic disease and the TH1/TH2 paradigm
Wynn, T. A. (2004) · Nature Reviews Immunology · doi:10.1038/nri1412 · Cited by 1,765
Self-citationHost Defense Mechanisms Triggered by Microbial Lipoproteins Through Toll-Like Receptors
Brightbill, H. D., Libraty, D. H., Krutzik, S. R., Yang, R., Belisle, J. T., Bleharski, J. R., Maitland, M. L., Norgard, M. V., Plevy, S. E., Smale, S. T., et al. (1999) · Science · doi:10.1126/science.285.5428.732 · Cited by 1,659 · cited 1×
“TLR and interferon pathways synergistically trigger NO production by transcriptional and post-transcriptional mechanisms that enhance expression of inducible nitric oxide synthase (iNOS), the enzyme responsible for NO production from arginine in macrophage”
BackgroundTranscriptional Adaptation of Mycobacterium tuberculosis within Macrophages
Schnappinger, D., Ehrt, S., Voskuil, M. I., Liu, Y., Mangan, J. A., Monahan, I. M., Dolganov, G., Efron, B., Butcher, P. D., Nathan, C., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030846 · Cited by 1,420
Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
Vats, D., Mukundan, L., Odegaard, J. I., Zhang, L., Smith, K. L., Morel, C. R., Greaves, D. R., Murray, P. J., & Chawla, A. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.011 · Cited by 1,369
Self-citationThe JAK-STAT Signaling Pathway: Input and Output Integration
Murray, P. J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.5.2623 · Cited by 1,179
Self-citationChan, J., Xing, Y., Magliozzo, R. S., & Bloom, B. R. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.175.4.1111 · Cited by 1,062
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Tiffney, E., Coombes, J. L., Legembre, P., & Flynn, R. J. (2022) · Microbes and Infection · doi:10.1016/j.micinf.2022.104952
Julius, D. J. (2014) · Annual Review of Physiology · doi:10.1146/annurev-ph-76-012314-100001
(1965) · Annual Review of Physiology · doi:10.1146/annurev.ph.27.020405.100001
Hoffman, J. F. (1990) · Annual Review of Physiology · doi:10.1146/annurev.ph.52.012706.100001
(1954) · Annual Review of Physiology · doi:10.1146/annurev.ph.16.020405.100001
Stevenson, M. M. (2011) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.12872959.14159057
(1941) · Annual Review of Physiology · doi:10.1146/annurev.ph.3.120304.100001
Julius, D. J. (2012) · Annual Review of Physiology · doi:10.1146/annurev-ph-74-021512-100001
Julius, D. J. (2015) · Annual Review of Physiology · doi:10.1146/annurev-ph-77-012815-100001
Hoffman, J. F. (1986) · Annual Review of Physiology · doi:10.1146/annurev.ph.48.020906.100001
Julius, D. J. (2011) · Annual Review of Physiology · doi:10.1146/annurev-ph-73-012611-100001
(1944) · Annual Review of Physiology · doi:10.1146/annurev.ph.6.120304.100001
Bento, C. A. (2020) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.46.2020.tde-28042022-140842
Shen, L., Sundstedt, A., Ciesielski, M. J., Miles, K. M., Celander, M., Adelaiye-Ogala, R. M., Orillion, A. R., Ciamporcero, E. S., Ramakrishnan, S., Ellis, L., et al. (2023) · doi:10.1158/2326-6066.c.6548818.v1
Valdés‐Fernández, B. N., Ruiz‐Jiménez, C., Armina-Rodríguez, A., Méndez, L. B., & Espino, A. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.10.552847
Fernandes, J. C. R. (2023) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.5.2023.tde-24082023-115843
РОЛЬ ОКСИДУ АЗОТУ ТА АРГІНІНУ ПРИ ЗАПАЛЬНИХ ЗАХВОРЮВАННЯХ СЕЧОСТАТЕВОЇ СИСТЕМИ ТА ПАТОСПЕРМІЇ
Мельник, О. В., Shykula, R. G., Павляк, У. В., Сус, М. Ю., & Коваленко, И. В. (2024) · Актуальні проблеми профілактичної медицини · doi:10.32782/2786-9067-2023-25-15
Papel de IL-1α na comorbidade obesidade e tuberculose
Apolloni, V. B. (2024) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.17.2024.tde-26072024-133224
Toxoplasma gondii: Cellular aspects of parasite
Costa, G. T., de Souza, I. S. R., de Oliveira, D. W., Souza, O. M. D. J., Afonso, C. M. C., de Carvalho, G. O. A. M., Seabra, S. H., & Fortes, F. D. S. D. A. (2025) · Research Society and Development · doi:10.33448/rsd-v14i1.48052
Crompton, R. A., Szondi, D. C., Doherty, C., Thomason, H. A., Lee, S. H., Loh, Y. P., O’Neill, C. A., Vardy, L. A., McBain, A. J., & Cruickshank, S. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.24.640016
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Zhao, S., Bao, M., & Cai, X. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.5c00232
Subverting Immunity From the Inside: Strategies of Intracellular Survival – Protozoans
Terrazas, C. A., Oghumu, S., Jha, B. K., Volpedo, G., Natarajan, G. K., Drew, M. E., Denkers, E., Satoskar, A. R., & McGwire, B. S. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00267-2
Rai, B., Barinberg, D., Liang, C., Debus, A., Rauh, M., Kirici, S., Sebald, H., Grotz, M., Gold, T., Kunz, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.23.677696
Self-citationShen, L. (2014) · doi:10.21236/ada615157
“An important regulator of Arg1 gene expression is TLR4 signaling (39), which is a receptor for a tasquinimod-target protein, S100A9.”
BackgroundYu, Y., Liu, X., Sun, J., Wang, R., Liu, H., Zhong, X., Jiang, L., Li, Y., & Nie, Z. (2026) · Talanta · doi:10.1016/j.talanta.2025.129340
Li, J., Yang, F., Ren, Z., Zhang, C., Xing, M., & Jiao, Z. (2026) · Stem Cell Research & Therapy · doi:10.1186/s13287-026-04981-y
“Conversely, M2 macrophages, associated with tissue repair and inflammation resolution, upregulate arginase-1 (Arg-1) and anti-inflammatory cytokines like IL-10 [12, 13].”
Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation
Kerndl, M., Musiejovsky, L., Komljenović, A., Lam, H. S., Vogel, A., Bausbacher, T., Riedl, C. J., Sango, R., Matejovicova, L., Dobrijević, A., et al. (2026) · Nature Immunology · doi:10.1038/s41590-026-02516-4
“Arg1 fl/fl mice (C57BL/6-Arg1 tm1Pmu /J, The Jackson Laboratory, 008817) were a kind gift of P. J. Murray (Immunoregulation Research Group, Max Planck Institute of Biochemistry, Germany) 81 and were crossed with Cx3cr1 -Cre mice (B6J.”
Ellappan, K., Joseph, N. M., Narasimhan, P. B., Garlant, H. N., Vasan, S., Jain, K., Kumar, S. V., Govindaraj, V., Negi, V. S., & Kempsell, K. E. (2026) · Tuberculosis · doi:10.1016/j.tube.2026.102795
Wu, P., Fu, B., Nan, D., Wen, Y., Wang, H., Zhang, Z., Rao, C., Lu, X., Wang, M., Sheng, Y., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117868
Wang, X., Ma, S., Ye, T., Guo, H., Wang, Y., Yan, X., Sun, Y., Zhao, M., Jiang, L., & Feng, L. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2026.1877832
“For example, Mycobacterium tuberculosis promotes the expression of arginase in mouse macrophages, resulting in decreased intracellular NO production and a weakened antibacterial response from the host (El Kasmi et al., 2008).”
Li, J.-L., Ge, S.-Y., Zhou, X.-X., Yan, R., Lin, K.-X., Wu, S., Qu, X.-D., Wang, N., Wu, J., & Shi, Y.-Q. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198528
Wang, Y., Shang, Y., Yu, H., 李昕潼, Ji, A., Wang, L., 陈吉林, & 戚钰 (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1892313
“The antibacterial effect of Arg1 is supported by tuberculosis and toxoplasmosis models (72), not by a direct comparison of bacterial killing in PRRSV-associated PAM states.”
Immunometabolism Responses upon Bacterial Metabolism
Gupta, R., & Singh, V. (2026) · Springer eBooks · doi:10.1007/978-3-032-30306-6_6
Peng, Q., & Yang, L. (2026) · Immunological Investigations · doi:10.1080/08820139.2026.2750409
STAT1-Regulated Lung MDSC-like Cells Aid Resolution of Inflammation After Bacterial Pneumonia
Poe, S. L. (2012) · D-Scholarship@Pitt (University of Pittsburgh)
Shweash, M. A. M. (2010) · OpenGrey (Institut de l'Information Scientifique et Technique) · doi:10.48730/je69-5959
Metadata
- Authors
- 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., Kaplan, G., Fitzgerald, K. A., Tuomanen, E. I., Orme, I. M., Kanneganti, T.-D., Bogdan, C., Wynn, T. A., & Murray, P. J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- National Institutes of Health (US)
- Colorado State University (US)
- University Medical Center Freiburg (DE)
- Universitätsklinikum Erlangen (DE)
- University of Medicine and Dentistry of New Jersey (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Wynn, Thomas A
- Murray, Peter J
- ORCID
- Venue
- Nature Immunology
- Published
- 2008-11-02
- Volume
- 9
- Issue
- 12
- Pages
- 1399-1406
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC2584974
- OpenAlex
- W2038461328
- Cited by
- 646
- References
- 50
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 19 · 2023: 33 · 2022: 25 · 2021: 48 · 2020: 34 · 2019: 35 · 2018: 32 · 2017: 29 · 2016: 52 · 2015: 51 · 2014: 52 · 2013: 49 · 2012: 39
- FWCI
- 13.66
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P30CA021765)
- National Institute of Allergy and Infectious Diseases (AI27913, R01AI027913, AI062921, R01AI066046, AI66046, R01AI062921)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- arginase-1, Toll-like receptor signaling, macrophages, intracellular pathogens, Mycobacterium tuberculosis, Toxoplasma gondii, nitric oxide, STAT6, host-pathogen interaction, tuberculosis, toxoplasmosis, lung bacterial load
- MeSH terms
- Animals, Arginase, Bacterial Infections, Immunohistochemistry, Macrophages, Immunoblotting, Mice, Knockout, CCAAT-Enhancer-Binding Protein-beta, STAT6 Transcription Factor, Toll-Like Receptors, Mice, Myeloid Differentiation Factor 88
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