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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
Cited by
Sorted by citations
Macrophage activation and polarization: nomenclature and experimental guidelines
Murray, P. J., Allen, J. E., Biswas, S. K., Fisher, E. A., Gilroy, D. W., Goerdt, S., Gordon, S., Hamilton, J. A., Ivashkiv, L. B., Lawrence, T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.008 · Cited by 6,337
“…has led to interpretive problems because Arg1 is also induced in M1 spectrum macrophages, expressed in some resident macrophage populations, and highly induced in mycobacteria-infected macrophages, further emphasizing the need for criteria encompassing multiple markers (El Kasmi et al., 2008).”
Self-citationProtective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269
Self-citationAlternative activation of macrophages: mechanism and functions
Gordon, S., & Martinez, F. O. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.007 · Cited by 4,197
“There are obvious caveats to the use of reverse analysis alone, as required in human studies in situ: substantial species differences exist in available markers, and established markers such as Arg1 can be induced by other pathways (El Kasmi et al., 2008).”
BackgroundMurray, P. J. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034339 · Cited by 2,981
“F or p er so na l u se o nl y. Table 1 (Continued ) Protein (gene)a Function Genetic lesionb Effect on polarization Reference(s) Notes IRF5 (Irf5) Transcription factor Conditional knockout (LysM-Cre) Complete knockout Loss of M1 65, 106 None TSC1 (Tsc1) Inhibitor of mTOR Conditional knockout (LysM-Cre) Gain of M1 Part…”
BackgroundInfluentialSelf-citationTranscriptional regulation of macrophage polarization: enabling diversity with identity
Lawrence, T., & Natoli, G. (2011) · Nature Reviews Immunology · doi:10.1038/nri3088 · Cited by 2,284
“Both STAT6 and C/EBPβ have recently been shown to be essential for arginase 1 expression in macrophages, but in a stimulus-specific manner owing to the selective use of distinct cis -acting elements in the Arg1 promote”
BackgroundThe transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L., Fitzgerald, P., Chi, H., Munger, J., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.021 · Cited by 2,140
“Arg1flox/flox; Tie2Cre mice that were backcrossed to the C57BL/6 background were obtained from P. Murray (SJCRH, Memphis) (El Kasmi et al., 2008).”
MethodMicroglial M1/M2 polarization and metabolic states
Orihuela, R., McPherson, C. A., & Harry, G. J. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13139 · Cited by 2,070
“In addition, the primary ‘marker’ for M2, Arg1, is also induced in M1 macrophages and expressed in some resident and mycobacteriainfected macrophages (El Kasmi et al., 2008).”
BackgroundMetabolic reprogramming in macrophages and dendritic cells in innate immunity
Kelly, B., & O'Neill, L. A. (2015) · Cell Research · doi:10.1038/cr.2015.68 · Cited by 1,876
Macrophages: master regulators of inflammation and fibrosis
Wynn, T., & Barron, L. (2010) · Seminars in Liver Disease · doi:10.1055/s-0030-1255354 · Cited by 1,392
“Given the presumably important contribution of AAMw to the development of fibrosis, a great deal of recent research has sought to identify the signals that regulate their activation and recruitment to sites of inflammation, with IL4, IL-13, IL-10, granulocyte-macrophage colony-stimulating factor, IL-21, prostaglandin…”
BackgroundResultSelf-citationMetabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages
Rath, M., ller, I. M. ⁄., Kropf, P., Closs, E. I., & Munder, M. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00532 · Cited by 1,332
“Another layer of complexity comes into play by the demonstration of pathogen-induced toll-like receptor (TLR)-mediated induction of arginase I in murine macrophages (67, 68).”
BackgroundResultM1 and M2 Macrophages: Oracles of Health and Disease
Mills, C. D. (2012) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v32.i6.10 · Cited by 1,169
Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989
Novel Markers to Delineate Murine M1 and M2 Macrophages
Jablonski, K. A., Amici, S. A., Webb, L. M., Ruiz-Rosado, J. D. D., Popovich, P. G., Partida-Sanchez, S., & Guerau-de-Arellano, M. (2015) · PLOS ONE · doi:10.1371/journal.pone.0145342 · Cited by 978
“Arginase-1 is up-regulated not only in the expected M2 macrophages but also in M1 spectrum macrophages [30,31].”
BackgroundResultNitric 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
Self-citationTumor-Induced Tolerance and Immune Suppression Depend on the C/EBPβ Transcription Factor
Marigo, I., Bosio, E., Solito, S., Mesa, C., Fernández, A., Dolcetti, L., Ugel, S., Sonda, N., Bicciato, S., Falisi, E., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.010 · Cited by 854
“Cg-Tg(Tek-Cre)1Ywa (Tie2 transgene abbreviated here as Tie2cre), as previously reported for other genes (El Kasmi et al., 2008).”
BackgroundArginase-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
“Recently, we showed that Arg1-expressing macrophages also regulate type-1 responses [8].”
BackgroundResultInfluentialSelf-citationDyken, S. J. V., & Locksley, R. M. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095906 · Cited by 743
“Importantly, although IL-4-mediated Arg1 induction in AAMs relies on STAT6 (42), Arg1 can also be induced by STAT3-dependent activation in the absence of other AAM markers after TLR stimulation or Mycobacterium tuberculosis infection, via signaling through the TLR adapter myeloid differentiation marker 88 (MyD88) and…”
Macrophage polarization in pathology
Sica, A., Erreni, M., Allavena, P., & Porta, C. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1995-y · Cited by 673
“Similar to other pathogens, including MT [124], H.”
Arginase: an emerging key player in the mammalian immune system
Munder, M. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00291.x · Cited by 725
“In contrast, murine viability in the context of sepsis models (by LPS challenge or Streptococcus pneumoniae inoculation) was unaltered in the context of macrophage arginase-deficiency (El Kasmi et al., 2008).”
BackgroundInfluentialMacrophages and cancer: from mechanisms to therapeutic implications
Ostuni, R., Kratochvill, F., Murray, P. J., & Natoli, G. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.004 · Cited by 709
Self-citationType 2 cytokines: mechanisms and therapeutic strategies
Wynn, T. A. (2015) · Nature reviews. Immunology · doi:10.1038/nri3831 · Cited by 683
Self-citationMacrophage phenotypes in atherosclerosis
Colin, S., Chinetti‐Gbaguidi, G., & Staels, B. (2014) · Immunological Reviews · doi:10.1111/imr.12218 · Cited by 657
“In response to TLR signaling, Arg1 induction is mediated by C/EBPb in murine macrophages (96).”
BackgroundTakeda, N., O'Dea, E. L., Doedens, A. L., Kim, J., Weidemann, A., Stockmann, C., Asagiri, M., Simon, M. C., Hoffmann, A., & Johnson, R. S. (2010) · Genes & Development · doi:10.1101/gad.1881410 · Cited by 646
Modulation of innate immunity by Toxoplasma gondii virulence effectors
Hunter, C. A., & Sibley, L. D. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2858 · Cited by 570
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 581
Self-citationMacrophage-Mediated Inflammation in Normal and Diabetic Wound Healing
Boniakowski, A. E., Kimball, A., Jacobs, B. N., Kunkel, S. L., & Gallagher, K. A. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700223 · Cited by 564
“These definitions are problematic, however, because Arg-1 is also expressed in both proinflammatory MoMFs and some trMFs (11).”
BackgroundMacrophage plasticity in experimental atherosclerosis
Khallou-Laschet, J., Varthaman, A., Fornasa, G., Compain, C., Gaston, A.-T., Clement, M., Dussiot, M., Levillain, O., Graff-Dubois, S., Nicoletti, A., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008852 · Cited by 517
“However, it has been shown that IFNc and LPS differently modulate Arg II expression in M1 MØ [8] and that Arg I can be expressed by MØ that have been activated independently of M2-polarizing conditions (IL-4/IL-13) [23,24].”
BackgroundSteggerda, S. M., Bennett, M. K., Chen, J., Emberley, E. D., Huang, T. C., Janes, J. R., Li, W., MacKinnon, A. L., Makkouk, A., Marguier, G. M., et al. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0308-4 · Cited by 503
“Secondly, genetic ablation of Arg1 in the myeloid compartment of tumor-bearing mice was shown to reduce tumor growth, indicative of a pro-tumorigenic and immune suppressive role for Arg1 in vivo [13, 14, 19, 32].”
BackgroundMethodSelf-citationRecent advances in arginine metabolism: roles and regulation of the arginases
Morris Jr, S. M. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00278.x · Cited by 485
“Thus, mouse strains with ablation of arginase I expression in macrophages have recently been developed to demonstrate the role of this enzyme in modulating host defense against intracellular pathogens (El Kasmi et al., 2008).”
BackgroundInnate immunity to Toxoplasma gondii infection
Yarovinsky, F. (2014) · Nature reviews. Immunology · doi:10.1038/nri3598 · Cited by 462
New Insights on the Role of Lipid Metabolism in the Metabolic Reprogramming of Macrophages
Batista‐González, A., Vidal, R. M., Criollo, A., & Carreño, L. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02993 · Cited by 443
“In general, it has been proposed that C/EBPα promotes M1 polarization, whereas C/EBPβ participates in M2 activation (69, 70), although several studies suggest that this distinction is more complicated (71, 72).”
BackgroundMyeloid Cell-Derived Arginase in Cancer Immune Response
Grzywa, T. M., Sosnowska, A., Matryba, P., Rydzyńska, Z., Jasiński, M., Nowis, D., & Gołąb, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00938 · Cited by 446
“Importantly, some intracellular pathogens induce expression of ARG1 in macrophages that hampers effective immune response (137).”
BackgroundLin, C., He, H., Liu, H., Li, R., Chen, Y., Qi, Y., Jiang, Q., Chen, L., Zhang, P., Zhang, H., et al. (2019) · Gut · doi:10.1136/gutjnl-2018-316324 · Cited by 420
Macrophages 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 427
RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming
Yin, H., Zhang, X., Yang, P., Zhang, X., Peng, Y., Li, D., Yu, Y., Wu, Y., Wang, Y., Zhang, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21514-8 · Cited by 412
Adenosine promotes alternative macrophage activation via A2A and A2B receptors
Csóka, B., Selmeczy, Z., Koscsó, B., Németh, Z. H., Pacher, P., Murray, P. J., Kepka‐Lenhart, D., Morris, S. M., Gause, W. C., Leibovich, S. J., et al. (2011) · The FASEB Journal · doi:10.1096/fj.11-190934 · Cited by 388
“Previous studies have proposed that arginase-1 promoter activity in macrophages is regulated by STAT-6 and C/EBP (31, 36, 47, 48).”
BackgroundSelf-citationArginine-dependent immune responses
Líndez, A.-A. M. I., & Reith, W. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03828-4 · Cited by 384
“tuberculosis coinfections with either Schistosoma mansoni or Toxoplasma gondii lead to increased Arg1 activity in lung macrophages and exacerbated disease progression [154, 155].”
BackgroundRegulation of inflammation by interleukin-4: a review of "alternatives"
Luzina, I. G., Keegan, A. D., Heller, N. M., Rook, G. A. W., Shea-Donohue, T., & Atamas, S. P. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0412214 · Cited by 351
“Both Mycobacterium tuberculosis and Toxoplasma gondii up-regulate arginase-1 in macrophages to induce the M2 macrophages [152] through a STAT6-independent, TLR-activated mechanism to circumnavigate”
BackgroundMattila, 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
“tuberculosis infection in mice (23, 24), likely reflecting depletion of L-arginine substrate for NO synthesis.”
BackgroundGundra, U. M., Girgis, N. M., Ruckerl, D., Jenkins, S., Ward, L. N., Kurtz, Z. D., Wiens, K. E., Tang, M. S., Basu-Roy, U., Mansukhani, A., et al. (2014) · Blood · doi:10.1182/blood-2013-08-520619 · Cited by 371
Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression
Kaneda, M. M., Cappello, P., Nguyen, A. V., Ralainirina, N., Hardamon, C. R., Foubert, P., Schmid, M. C., Sun, P., Mose, E. S., Bouvet, M., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1346 · Cited by 338
Metabolic origins of spatial organization in the tumor microenvironment
Carmona‐Fontaine, C., Déforet, M., Akkari, L., Thompson, C. B., Joyce, J. A., & Xavier, J. B. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700600114 · Cited by 335
“S4 C and D), such as Arg1 and Nos2 coexpression (34).”
BackgroundMetabolic orchestration of the wound healing response
Eming, S. A., Murray, P. J., & Pearce, E. J. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.07.017 · Cited by 326
Self-citationMuraille, É., Léo, O., & Moser, M. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00603 · Cited by 321
“These observations suggest that chronic infection could be linked to pathogen-induced Arg1 expression (37).”
BackgroundControl 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 321
“gondii challenge and decreased lung bacterial load during tuberculosis infection (56).”
BackgroundMicrobial manipulation of receptor crosstalk in innate immunity
Hajishengallis, G., & Lambris, J. D. (2011) · Nature reviews. Immunology · doi:10.1038/nri2918 · Cited by 307
“tuberculosis and Toxoplasma gondii were shown to promote their survival and ability to cause disease in mouse models through MYD88-dependent induction of macrophage arginase 1 (ARG1), which inhibits nitric oxide production by macrophages by competing with iNOS for the common substrate, arginin”
Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss
Matheis, F., Muller, P. A., Graves, C. L., Gabanyi, I., Kerner, Z. J., Costa-Borges, D., Ahrends, T., Rosenstiel, P. C., & Mucida, D. (2020) · Cell · doi:10.1016/j.cell.2019.12.002 · Cited by 312
Tet2 restrains inflammatory gene expression in macrophages
Cull, A. H., Snetsinger, B., Buckstein, R., Wells, R. A., & Rauh, M. J. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.08.001 · Cited by 295
Yang, Z., & Ming, X.-F. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00533 · Cited by 290
Alternatively activated macrophages in infection and autoimmunity
Fairweather, D., & Cihakova, D. (2009) · Journal of Autoimmunity · doi:10.1016/j.jaut.2009.09.012 · Cited by 290
TSC1 controls macrophage polarization to prevent inflammatory disease
Zhu, L., Yang, T., Li, L., Sun, L., Hou, Y., Hu, X., Zhang, L., Tian, H., Zhao, Q., Peng, J., et al. (2014) · Nature Communications · doi:10.1038/ncomms5696 · Cited by 287
Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis
Takeda, Y., Costa, S., Delamarre, E., Roncal, C., de Oliveira, R. L., Squadrito, M. L., Finisguerra, V., Deschoemaeker, S., Bruyére, F., Wenes, M., et al. (2011) · Nature · doi:10.1038/nature10507 · Cited by 290
Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity
Rodrı́guez, P. C., Ochoa, A. C., & Al-Khami, A. A. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00093 · Cited by 298
“Multiple other factors also induce the expression of arginase 1, including IL-10 (27), granulocyte-macrophage colony-stimulating factor (GM-CSF) (28), transforming growth factor β (TGFβ) (29), prostaglandin E2 (PGE2) (30), cyclic adenosine monophosphate (cAMP) (31), and toll-like receptor (TLR) agonists (32).”
BackgroundButcher, B. A., Fox, B. A., Rommereim, L. M., Kim, S. G., Maurer, K. J., Yarovinsky, F., Herbert, D. R., Bzik, D. J., & Denkers, E. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002236 · Cited by 282
“signaling cascade was of interest because arginase-1 competes with iNOS for the amino acid substrate arginine [38,39,40].”
BackgroundEffect of helminth-induced immunity on infections with microbial pathogens
Salgame, P., Yap, G. S., & Gause, W. C. (2013) · Nature Immunology · doi:10.1038/ni.2736 · Cited by 293
TNF Counterbalances the Emergence of M2 Tumor Macrophages
Kratochvill, F., Neale, G. A. M., Haverkamp, J. M., de Velde, L.-A. V., Smith, A. M., Kawauchi, D., McEvoy, J. D., Roussel, M. F., Dyer, M. A., Qualls, J. E., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.08.033 · Cited by 291
“Arg1flox/flox mice have been described elsewhere and were crossed to Tie2-Cre mice (El Kasmi et al., 2008).”
BackgroundMethodSelf-citationContribution of metabolic reprogramming to macrophage plasticity and function
Kasmi, K. C. E., & Stenmark, K. R. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.09.001 · Cited by 281
Grainger, J. R., Wohlfert, E. A., Fuss, I. J., Bouladoux, N. J., Askenase, M. H., Legrand, F., Koo, L. Y., Brenchley, J. M., Fraser, I. D. C., & Belkaid, Y. (2013) · Nature Medicine · doi:10.1038/nm.3189 · Cited by 259
Allen, J. E., & Sutherland, T. E. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.06.003 · Cited by 279
Guilliams, M., Lambrecht, B. N., & Hammad, H. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.14 · Cited by 276
“As such, Arginase / mice were shown to have an increased production of NO and to be more resistant to Mtb infection.(125) On the other hand, TNF may be crucial for two reasons.”
BackgroundKasmi, 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
“phage product with important roles in tissue remodeling, including PH, and is thought to be a functional hallmark of AAM (48, 56), we examined the mechanism of its expression in fibroblast-”
BackgroundMethodInfluentialAmino acid auxotrophy as a system of immunological control nodes
Murray, P. J. (2016) · Nature Immunology · doi:10.1038/ni.3323 · Cited by 254
Self-citationDas, P., Lahiri, A., Lahiri, A., & Chakravortty, D. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000899 · Cited by 247
“Mice lacking arginase I did not lose weight and did not show any sign of toxoplasmosis, unlike the control mice [19].”
BackgroundLocal Arginase 1 Activity Is Required for Cutaneous Wound Healing
Campbell, L., Saville, C. R., Murray, P. J., Cruickshank, S. M., & Hardman, M. J. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.164 · Cited by 254
“…primer sequenceForward primer sequenceTarget Gene”
Self-citationToxoplasma Polymorphic Effectors Determine Macrophage Polarization and Intestinal Inflammation
Jensen, K. D. C., Wang, Y., Wojno, E. D. T., Shastri, A. J., Hu, K. H., Cornel, L., Boedec, E., Ong, Y.-C., Chien, Y., Hunter, C. A., et al. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.04.015 · Cited by 236
“In keeping with an earlier report that Toxoplasma can induce the expression of Arg1 independently of STAT6 (El Kasmi et al., 2008), Toxoplasma elicited urea production in Stat6 / BMDMs, albeit at levels much lower than in wild-type BMDMs (Figure 3B).”
BackgroundResultInfluentialSingle cell RNA sequencing identifies unique inflammatory airspace macrophage subsets
Mould, K. J., Jackson, N. D., Henson, P. M., Seibold, M. A., & Janssen, W. J. (2019) · JCI Insight · doi:10.1172/jci.insight.126556 · Cited by 247
Kieler, M., Hofmann, M., & Schabbauer, G. (2021) · FEBS Journal · doi:10.1111/febs.15715 · Cited by 250
The Roles of Hypoxia Signaling in the Pathogenesis of Cardiovascular Diseases
Abe, H., Semba, H., & Takeda, N. (2017) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17009 · Cited by 244
Advanced Age Impairs Macrophage Polarization
Mahbub, S., Deburghgraeve, C. R., & Kovacs, E. J. (2012) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2011.0058 · Cited by 222
Whyte, C. S., Bishop, E., Rückerl, D., Gaspar-Pereira, S., Barker, R. N., Allen, J. E., Rees, A. J., & Wilson, H. M. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.1110644 · Cited by 226
“Enhanced arginase I expression is linked to M2 macrophages but is also induced in M1 macrophages through a MyD88-dependent pathway [39].”
BackgroundKasmi, K. E., Anderson, A. L., Devereaux, M., Vue, P. M., Zhang, W.-J., Setchell, K., Karpen, S., & Sokol, R. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006898 · Cited by 201
“Mouse BMDMs were generated from 6- to 8-week-old male C57BL/6 mice (Jackson Laboratories) as previously described (44).”
MethodActivation of Murine Macrophages
Mosser, D. M., & Zhang, X. (2008) · Current Protocols in Immunology · doi:10.1002/0471142735.im1402s83 · Cited by 222
Potian, J. A., Rafi, W., Bhatt, K., McBride, A., Gause, W. C., & Salgame, P. R. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20091473 · Cited by 214
“Indeed, mice lacking arg-1 exhibit a reduction in lung bacterial burden in comparison with WT mice (El Kasmi et al., 2008).”
ResultHuber, S., Hoffmann, R. F. G., Muskens, F., & Voehringer, D. (2010) · Blood · doi:10.1182/blood-2010-02-271981 · Cited by 205
Marigo, I., Zilio, S., Desantis, G., Mlecnik, B., Agnellini, A. H. R., Ugel, S., Sasso, M. S., Qualls, J. E., Kratochvill, F., Zanovello, P., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.08.004 · Cited by 205
“ARG1 can also compete with NOS2 for L-arginine and thus limit the overall ability of activated myeloid cells to generate NO (Bronte and Zanovello, 2005; El Kasmi et al., 2008).”
InfluentialSelf-citationShirey, K. A., Pletneva, L. M., Puche, A. C., Keegan, A. D., Prince, G. A., Blanco, J. C. G., & Vogel, S. N. (2010) · Mucosal Immunology · doi:10.1038/mi.2010.6 · Cited by 209
Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection
Marino, S., Cilfone, N. A., Mattila, J. T., Linderman, J. J., Flynn, J. L., & Kirschner, D. E. (2014) · Infection and Immunity · doi:10.1128/iai.02494-14 · Cited by 201
Image based Machine Learning for identification of macrophage subsets
Rostam, H. M., Reynolds, P. M., Alexander, M. R., Gadegaard, N., & Ghaemmaghami, A. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-03780-z · Cited by 196
Hossain, D. M. S., Pal, S. K., Moreira, D., Duttagupta, P. A., Zhang, Q., Won, H., Jones, J. O., D’Apuzzo, M., Forman, S. J., & Kortylewski, M. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3145 · Cited by 192
“Other studies in mouse tumor models showed that activation of TLRs in myeloid cells can in fact promote expression of immunosuppressive molecules critical for MDSC function, such as Arginase-1, S100A8, IL10, and PGE2 (19, 43–45).”
Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-κB signaling
Chiang, C., Chao, T., Su, Y., Hsu, C., Chien, C., Chiu, K., Shiah, S., Lee, C.-H., Liu, S.-Y., & Shieh, Y. (2017) · Oncotarget · doi:10.18632/oncotarget.14982 · Cited by 188
“For example, Argianse-1, despite being considered a classic M2 marker, was found to be up-regulated in M1 macrophages [28, 29].”
Background“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels
Nairz, M., Theurl, I., Swirski, F. K., & Weiss, G. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1944-8 · Cited by 178
“In contrast, arginase-1, which depletes the Nos2 substrate arginine by converting it to ornithine [62, 205], is reduced by heme.”
BackgroundMahajan, S., Dkhar, H. K., Chandra, V., Dave, S., Nanduri, R., Janmeja, A. K., Agrewala, J. N., & Gupta, P. K. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103038 · Cited by 185
“Whereas the levels of NO generated were identical to the reported levels for human macrophages (28), they were much less when compared with murine macrophages (25).”
BackgroundResultInfluentialQualls, J. E., Subramanian, C., Rafi, W., Smith, A. M., Balouzian, L., DeFreitas, A. A., Shirey, K. A., Reutterer, B., Kernbauer, E., Stockinger, S., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.07.012 · Cited by 184
“Some intracellular pathogens have harnessed this pathway as a survival mechanism by inducing Arg1 in both the infected and surrounding tissue (El Kasmi et al., 2008; Qualls et al., 2010).”
BackgroundSelf-citationMacrophage activation governs schistosomiasis‐induced inflammation and fibrosis
Barron, L., & Wynn, T. A. (2011) · European Journal of Immunology · doi:10.1002/eji.201141869 · Cited by 185
Self-citationTraumatic brain injury induces macrophage subsets in the brain
Hsieh, C. L., Kim, C. C., Ryba, B. E., Niemi, E. C., Bando, J. K., Locksley, R. M., Liu, J., Nakamura, M. C., & Seaman, W. E. (2013) · European Journal of Immunology · doi:10.1002/eji.201243084 · Cited by 185
“In this regard, Arg1 expression can be induced by pathways independent of IL–4/STAT6 [51].”
BackgroundBaghdadi, M., Wada, H., Nakanishi, S., Abe, H., Han, N., Putra, W. E., Endo, D., Watari, H., Sakuragi, N., Hida, Y., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1170 · Cited by 188
“In particular, C/EBPb has been shown to be essential for the expression of immunosuppressive cytokines such as IL10 and Arginase-1 (ARG1) in M2polarized macrophages (34).”
BackgroundThe role of polyamines in the regulation of macrophage polarization and function
Latour, Y. L., Gobert, A. P., & Wilson, K. T. (2019) · Amino Acids · doi:10.1007/s00726-019-02719-0 · Cited by 182
Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine
Bando, J. K., Liang, H.-E., & Locksley, R. M. (2014) · Nature Immunology · doi:10.1038/ni.3057 · Cited by 179
Arginase 1 is a key driver of immune suppression in pancreatic cancer
Menjivar, R. E., Nwosu, Z. C., Du, W., Donahue, K. L., Hong, H. S., Espinoza, C. E., Brown, K. L., Velez-Delgado, A., Yan, W., Lima, F., et al. (2023) · eLife · doi:10.7554/elife.80721 · Cited by 189
Wager, C. M. L., & Wormley, F. L. (2014) · Mucosal Immunology · doi:10.1038/mi.2014.65 · Cited by 171
Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection
Shi, L., Jiang, Q., Bushkin, Y., Subbian, S., & Tyagi, S. (2019) · mBio · doi:10.1128/mbio.02550-18 · Cited by 173
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 169
Self-citationOhashi, T., Akazawa, T., Aoki, M., Kuze, B., Mizuta, K., Ito, Y., & Inoue, N. (2013) · International Journal of Cancer · doi:10.1002/ijc.28114 · Cited by 168
“A previous report showed that the TLR ligand and IL-4 activate different signaling pathways to induce ARG1 expression.(36) Therefore, ARG1 expression induced by lactic acid and IL-4 could be induced via the activation of different signaling pathways.”
BackgroundLactate and IL6 define separable paths of inflammatory metabolic adaptation
Dichtl, S., Lindenthal, L., Zeitler, L., Behnke, K., Schlösser, D., Strobl, B., Scheller, J., Kasmi, K. C. E., & Murray, P. J. (2021) · Science Advances · doi:10.1126/sciadv.abg3505 · Cited by 169
Self-citationSchreiber, 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 165
“Therefore, IL-10 is *Infection Immunology and †Microbial Inflammation Research, Research Center Borstel, Borstel, Germany; ‡Molecular Inflammation Medicine, Christian Albrechts University, Kiel, Germany; §Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany; ¶Departme…”
BackgroundInfluentialSelf-citationSahu, S. K., Kumar, M., Chakraborty, S., Banerjee, S. K., Kumar, R., Gupta, P., Jana, K., Gupta, U. D., Ghosh, Z., Kundu, M., et al. (2017) · PLOS Pathogens · doi:10.1371/journal.ppat.1006410 · Cited by 158
Arnold, C. E., Whyte, C. S., Gordon, P., Barker, R. N., Rees, A. J., & Wilson, H. M. (2013) · Immunology · doi:10.1111/imm.12173 · Cited by 163
Sahin, E., Haubenwallner, S., Kuttke, M., Kollmann, I., Halfmann, A., Dohnal, A. M., Chen, L., Cheng, P. P., Hoesel, B., Einwallner, E., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302167 · Cited by 159
“To study the contribution of other candidate TFs, besides STAT6, we analyzed the involvement of C/EBPb, which has been shown to contribute to pattern recognition receptor–mediated regulation of Arginase I (16).”
BackgroundArginine Metabolism in Bacterial Pathogenesis and Cancer Therapy
Xiong, L., Teng, J. L. L., Botelho, M. G., Lo, R. C., Lau, S. K. P., & Woo, P. C. Y. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17030363 · Cited by 157
“Arginase has also been shown to be involved in bacterial infection caused by Mycobacterium tuberculosis [35,36], parasitic infection caused by Trypanosoma cruzi [37], and fungal infection caused by Candida albicans [38], implying the critical role of arginase for other infections.”
BackgroundMacrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas
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., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408839111 · Cited by 146
“(22) demonstrated improved control of Mtb in the lung.”
BackgroundResultInfluentialSelf-citation
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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