The Hydroxylase Inhibitor Dimethyloxallyl Glycine Attenuates Endotoxic Shock Via Alternative Activation of Macrophages and IL-10 Production by B1 Cells
Open accessAbstract
Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors hypoxia-inducible factor 1α and nuclear factor κB (NF-κB) via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of hypoxia-inducible factor 1 and NF-κB. We have demonstrated in vivo that pretreatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. Dimethyloxallyl glycine treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of proinflammatory cytokines such as TNF-α. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B1 cell population. This study demonstrates cell type-specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock.
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HIF activators elicit an M2-like macrophage phenotype.
“HIF activators appear capable of triggering multiple tissue protective pathways that protect epithelial cells from apoptosis, elicit an M2-like macrophage phenotype, and induce IL-10 production in B cells [119, 120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [120]
HIF activators limit inflammation in models of inflammatory bowel disease and LPS-induced shock.
“and to limit inflammation in models of inflammatory bowel disease and LPS-induced shock [117–120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [120]
HIF activation protects against LPS-induced shock.
“while HIF activation protects against LPS-induced shock, it is deleterious in mice subjected to polymicrobial sepsis following cecal ligation puncture [120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [120]
HIF activators protect epithelial cells from apoptosis.
“HIF activators appear capable of triggering multiple tissue protective pathways that protect epithelial cells from apoptosis, elicit an M2-like macrophage phenotype, and induce IL-10 production in B cells [119, 120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [120]
HIF activation is deleterious in mice subjected to polymicrobial sepsis following cecal ligation puncture.
“while HIF activation protects against LPS-induced shock, it is deleterious in mice subjected to polymicrobial sepsis following cecal ligation puncture [120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [120]
HIF activators induce IL-10 production in B cells.
“HIF activators appear capable of triggering multiple tissue protective pathways that protect epithelial cells from apoptosis, elicit an M2-like macrophage phenotype, and induce IL-10 production in B cells [119, 120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [120]
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Cites
1 retracted
Frede, S., Stockmann, C., Winning, S., Freitag, P., & Fandrey, J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0802378 · Cited by 35 · see citing works
RetractedMonocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190 · see citing works
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · cited 1× · see citing works
“sensitivity of which is conferred by a family of O2-dependent hydroxylases (4).”
Sepsis in European intensive care units: Results of the SOAP study*
Vincent, J., Sakr, Y. L., Sprung, C. L., Ranieri, V. M., Reinhart, K., Gerlach, H., Moreno, R. P., Carlet, J. M., Gall, J. L., & Payen, D. M. (2006) · Critical Care Medicine · doi:10.1097/01.ccm.0000194725.48928.3a · Cited by 2,823 · see citing works
Eltzschig, H. K., & Carmeliet, P. (2011) · New England Journal of Medicine · doi:10.1056/nejmra0910283 · Cited by 2,061 · see citing works
NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., Johnson, R. S., Haddad, G. G., & Karin, M. (2008) · Nature · doi:10.1038/nature06905 · Cited by 1,614 · see citing works
Endotoxin tolerance: new mechanisms, molecules and clinical significance
Biswas, S. K., & Lopez-Collazo, E. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.07.009 · Cited by 1,318 · see citing works
Bacterial lipopolysaccharides and innate immunity
Alexander, C., & Rietschel, E. T. (2001) · Journal of Endotoxin Research · doi:10.1179/096805101101532675 · Cited by 1,173 · see citing works
Satoh, T., Takeuchi, O., Vandenbon, A., Yasuda, K., Tanaka, Y., Kumagai, Y., Miyake, T., Matsushita, K., Okazaki, T., Saitoh, T., et al. (2010) · Nature Immunology · doi:10.1038/ni.1920 · Cited by 1,156 · see citing works
Hypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity
Walmsley, S. R., Print, C., Farahi, N., Peyssonnaux, C., Johnson, R. S., Cramer, T., Sobolewski, A., Condliffe, A. M., Cowburn, A. S., Johnson, N., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20040624 · Cited by 891 · see citing works
Cummins, E. P., Berra, E., Comerford, K. M., Ginouves, A., Fitzgerald, K. T., Seeballuck, F., Godson, C., Nielsen, J. E., Moynagh, P., Pouyssegur, J., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602235103 · Cited by 788 · see citing works
Self-citationInterdependence of hypoxic and innate immune responses
Nizet, V., & Johnson, R. S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2607 · Cited by 708 · see citing works
Oxidation in rheumatoid arthritis.
Hitchon, C. A., & El-Gabalawy, H. S. (2004) · Arthritis Research · doi:10.1186/ar1447 · Cited by 583 · see citing works
Peyssonnaux, C., Cejudo-Martin, P., Doedens, A., Zinkernagel, A. S., Johnson, R. S., & Nizet, V. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.12.7516 · Cited by 480 · see citing works
Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB
Frede, S., Stockmann, C., Freitag, P., & Fandrey, J. (2006) · Biochemical Journal · doi:10.1042/bj20051839 · Cited by 436 · see citing works
The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis
Cummins, E. P., Seeballuck, F., Keely, S. J., Mangan, N. E., Callanan, J. J., Fallon, P. G., & Taylor, C. T. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.10.012 · Cited by 407 · see citing works
Self-citationKamanaka, M., Kim, S. T., Wan, Y. Y., Sutterwala, F. S., Lara-Tejero, M., Galán, J. E., Harhaj, E., & Flavell, R. A. (2006) · Immunity · doi:10.1016/j.immuni.2006.09.013 · Cited by 392 · see citing works
Interdependent roles for hypoxia inducible factor and nuclear factor‐κB in hypoxic inflammation
Taylor, C. T. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.157669 · Cited by 354 · see citing works
Self-citationHelminth Infection Protects Mice from Anaphylaxis via IL-10-Producing B Cells1
Mangan, N. E., Fallon, R., Smith, P., van Rooijen, N., McKenzie, A., & Fallon, P. (2004) · Journal of Immunology · doi:10.4049/jimmunol.173.10.6346 · Cited by 321 · see citing works
Self-citationSeasonal variation in the epidemiology of sepsis*
Danai, P. A., Sinha, S., Moss, M. M., Haber, M., & Martin, G. S. (2006) · Critical Care Medicine · doi:10.1097/01.ccm.0000253405.17038.43 · Cited by 199 · see citing works
Thiel, M., Caldwell, C. C., Kreth, S., Kuboki, S., Chen, P., Smith, P., Ohta, A., Lentsch, A. B., Lukashev, D., & Sitkovsky, M. V. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000853 · Cited by 175 · see citing works
Upregulation of Hypoxia-Inducible Factors in Normal and Psoriatic Skin
Rosenberger, C., Solovan, C. S., Rosenberger, A. D., Li, J., Treudler, R., Frei, U. A., Eckardt, K., & Brown, L. F. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700874 · Cited by 156 · see citing works
Fitzpatrick, S. F., Tambuwala, M. M., Brüning, U., Schaible, B., Scholz, C. C., Byrne, A. T., O’Connor, A. E., Gallagher, W. M., Lenihan, C. R., Garvey, J., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1002256 · Cited by 153 · see citing works
Self-citationSiewe, L., Bollati‐Fogolín, M., Wickenhauser, C., Krieg, T. M., Müller, W., & Roers, A. (2006) · European Journal of Immunology · doi:10.1002/eji.200636012 · Cited by 126 · see citing works
Orchestration of macrophage polarization
Mantovani, A., & Locati, M. (2009) · Blood · doi:10.1182/blood-2009-07-231795 · Cited by 115 · see citing works
Magness, S. T., Jijon, H. B., Fisher, N. V. H., Sharpless, N. E., Brenner, D. A., & Jobin, C. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.3.1561 · Cited by 113 · see citing works
Self-citationHirota, S. A., Fines, K., Ng, J., Traboulsi, D., Lee, J., Ihara, E., Li, Y., Willmore, W. G., Chung, D. C., Scully, M. M., et al. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.03.045 · Cited by 100 · see citing works
Chan, G. C. T., Bivins-Smith, E. R., Smith, M. S., & Yurochko, A. D. (2009) · Virus Research · doi:10.1016/j.virusres.2009.04.026 · Cited by 79 · see citing works
Attenuation of myocardial injury by postconditioning: role of hypoxia inducible factor-1α
Zhao, H., Wang, X., Wang, Y., Wu, Y., Li, X., Lv, X., Zhao, Z., Zhao, R., & Liu, H. (2009) · Basic Research in Cardiology · doi:10.1007/s00395-009-0044-0 · Cited by 79 · see citing works
Xue, J., Thippegowda, P. B., Hu, G., Bachmaier, K., Christman, J. W., Malik, A. B., & Tiruppathì, C. (2009) · Physiological Genomics · doi:10.1152/physiolgenomics.00012.2009 · Cited by 75 · see citing works
Hindryckx, P., De Vos, M., Jacques, P., Ferdinande, L., Peeters, H., Olievier, K., Bogaert, S., Brinkman, B., Vandenabeele, P., Elewaut, D., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1002541 · Cited by 73 · see citing works
Takeda, K., Ichiki, T., Narabayashi, E., Inanaga, K., Miyazaki, R., Hashimoto, T., Matsuura, H., Ikeda, J., Miyata, T., & Sunagawa, K. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.196071 · Cited by 68 · see citing works
C-Type Lectin SIGN-R1 Has a Role in Experimental Colitis and Responsiveness to Lipopolysaccharide
Saunders, S. P., Barlow, J. L., Walsh, C. M., Bellsoi, A., Smith, P., McKenzie, A. N. J., & Fallon, P. G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901970 · Cited by 53 · see citing works
Self-citationB-1 cells temper endotoxemic inflammatory responses
Barbeiro, D. F., Barbeiro, H. V., Faintuch, J., Ariga, S. K. K., Mariano, M., Popi, A. F., de Souza, H. P., Velasco, I. T., & Soriano, F. G. (2010) · Immunobiology · doi:10.1016/j.imbio.2010.08.002 · Cited by 45 · see citing works
Murine Model of Polymicrobial Septic Peritonitis Using Cecal Ligation and Puncture (CLP)
Medina, E. (2009) · Methods in molecular biology · doi:10.1007/978-1-60761-058-8_23 · Cited by 35 · see citing works
Convergent pathways of macrophage polarization: The role of B cells
Sica, A., Porta, C., Riboldi, E., & Locati, M. (2010) · European Journal of Immunology · doi:10.1002/eji.201040736 · Cited by 27 · see citing works
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Ngwa, W., Irabor, O. C., Schoenfeld, J. D., Hesser, J., Demaria, S., & Formenti, S. C. (2018) · Nature Reviews Cancer · doi:10.1038/nrc.2018.6 · Cited by 1,260 · see citing works
The role of HIF in immunity and inflammation
McGettrick, A. F., & O’Neill, L. A. J. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.08.002 · Cited by 768 · see citing works
Regulation of Immunity and Inflammation by Hypoxia in Immunological Niches
Taylor, C. T., & Colgan, S. P. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.103 · Cited by 713 · see citing works
Self-citationMcNamee, E. N., Korns Johnson, D., Homann, D., & Clambey, E. T. (2013) · Immunologic Research · doi:10.1007/s12026-012-8349-8 · Cited by 234 · see citing works
Scholz, C. C., Cavadas, M. A. S., Tambuwala, M. M., Hams, E., Rodríguez, J., Kriegsheim, A. V., Cotter, P., Bruning, U., Fallon, P. G., Cheong, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309718110 · Cited by 186 · see citing works
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- Authors
- Hams, E., Saunders, S. P., Cummins, E. P., O'Connor, A., Tambuwala, M. T., Gallagher, W. M., Byrne, A., Campos-Torres, A., Moynagh, P. M., Jobin, C., Taylor, C. T., & Fallon, P. G.
- Affiliations
- Trinity College (CA)
- University College Dublin (IE)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Hams, Emily
- Saunders, Sean P.
- Fallon, Padraic G.
- ORCID
- Venue
- Shock
- Published
- 2011-09
- Volume
- 36
- Issue
- 3
- Pages
- 295-302
- ISSN
- 1073-2322 (ISSN-L)
- PMC
- PMC3157050
- OpenAlex
- W1619977460
- Cited by
- 106
- References
- 36
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 12 · 2017: 5 · 2016: 10 · 2015: 9 · 2014: 7 · 2013: 9 · 2012: 2
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- green
- pure.ulster.ac.uk
- Licence
- other-oa
- Locations
- Shock (publishedVersion)
- PubMed (publishedVersion)
- Ulster University Research Portal (Ulster University) (publishedVersion, other-oa)
- Maynooth University ePrints and eTheses Archive (Maynooth University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Lincoln Repository (University of Lincoln) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- UNC Libraries
- Funders
- Science Foundation Ireland (07/IN.1/B902)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK047700)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- endotoxic shock, sepsis, NF-κB signaling, hypoxia-inducible factor-1α, M2 macrophage polarization, IL-10, B-1 cells, lipopolysaccharide, TNF-α, polymicrobial sepsis, oxygen sensing
- MeSH terms
- Amino Acids, Dicarboxylic, Animals, Flow Cytometry, Mixed Function Oxygenases, Lipopolysaccharides, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Shock, Septic, Immunoblotting, Polymerase Chain Reaction, NF-kappa B, Interleukin-10, Sepsis, Mice, Receptors, Interleukin-10
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