Endotoxin tolerance: new mechanisms, molecules and clinical significance
Abstract
Prior exposure of innate immune cells like monocytes/macrophages to minute amounts of endotoxin cause them to become refractory to subsequent endotoxin challenge, a phenomenon called "endotoxin tolerance". Clinically, this state is associated with monocytes/macrophages in sepsis patients where they contribute to "immunosuppression" and mortality. The molecular mechanisms underlying endotoxin tolerance remain elusive. The recent appreciation of inflammation as a self-regulating process, the relative contribution of MyD88 versus TRIF signaling pathways in inducing activation or tolerance, plasticity of NF-kappaB function and the role of chromatin modification and microRNAs in LPS-induced gene reprogramming urges a re-evaluation of endotoxin tolerance. This review integrates these new findings into an up-to-date account of endotoxin tolerance, its molecular basis and clinical implications in different pathologies.
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?
LPS-stimulated classically activated macrophages become TLR-tolerant and unable to produce similarly elevated pro-inflammatory cytokines upon second LPS exposure, but retain ability to produce anti-inflammatory cytokines like IL-10.
“For example, in vitro experiments have shown that LPS stimulated, classically activated macrophages, become Toll-like receptor (TLR)-tolerant and unable to produce similarly elevated levels of pro-inflammatory cytokines upon second exposure to LPS [16–18].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [17]
Cites
Taganov, K. D., Boldin, M. P., Chang, K.-J., & Baltimore, D. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605298103 · Cited by 4,317 · see citing works
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · see citing works
Macrophage Polarization Comes of Age
Mantovani, Sica, & Locati, M. (2005) · Immunity · doi:10.1016/j.immuni.2005.10.001 · Cited by 1,259 · see citing works
Resolution of in flammation: state of the art, definitions and terms
Serhan, C. N., Brain, S. D., Buckley, C. D., Gilroy, D. W., Haslett, C., O'Neill, L. A. J., Perretti, M., Rossi, A. G., & Wallace, J. L. (2007) · The FASEB Journal · doi:10.1096/fj.06-7227rev · Cited by 1,045 · see citing works
Bazzoni, F., Rossato, M., Fabbri, M., Gaudiosi, D., Mirolo, M., Mori, L., Tamassia, N., Mantovani, A., Cassatella, M. A., & Locati, M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810909106 · Cited by 548 · see citing works
Litvak, V., Ramsey, S. A., Rust, A. G., Zak, D. E., Kennedy, K. A., Lampano, A. E., Nykter, M., Shmulevich, I., & Aderem, A. (2009) · Nature Immunology · doi:10.1038/ni.1721 · Cited by 295 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840 · see citing works
Self-citationSepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy
Hotchkiss, R. S., Monneret, G., & Payen, D. (2013) · Nature Reviews Immunology · doi:10.1038/nri3552 · Cited by 2,772 · see citing works
Diversity, Mechanisms, and Significance of Macrophage Plasticity
Locati, M., Curtale, G., & Mantovani, A. (2020) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012418-012718 · Cited by 2,199 · see citing works
Transcriptional regulation of macrophage polarization: enabling diversity with identity
Lawrence, T., & Natoli, G. (2011) · Nature Reviews Immunology · doi:10.1038/nri3088 · Cited by 2,284 · see citing works
From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation
Italiani, P., & Boraschi, D. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00514 · Cited by 2,067 · see citing works
Microglial <scp>M1/M2</scp> 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 · see citing works
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity
Saeed, S., Quintin, J., Kerstens, H. H. D., Rao, N. A., Aghajanirefah, A., Matarese, F., Cheng, S.-C., Ratter, J., Berentsen, K., van der Ent, M. A., et al. (2014) · Science · doi:10.1126/science.1251086 · Cited by 1,761 · see citing works
Neuroinflammation: The Devil Is in the Details
DiSabato, D. J., Quan, N., & Godbout, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13607 · Cited by 1,640 · see citing works
Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans
Vatanen, T., Kostic, A. D., d’Hennezel, E., Siljander, H., Franzosa, E. A., Yassour, M., Kolde, R., Vlamakis, H., Arthur, T. D., Hämäläinen, A.-M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.007 · Cited by 1,289 · see citing works
α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
Liu, P.-S., Wang, H., Li, X., Chao, T., Teav, T., Christen, S., Di Conza, G., Cheng, W.-C., Chou, C.-H., Vavakova, M., et al. (2017) · Nature Immunology · doi:10.1038/ni.3796 · Cited by 1,264 · see citing works
Cirrhosis-associated immune dysfunction: Distinctive features and clinical relevance
Albillos, A., Lario, M., & Álvarez-Mon, M. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.08.010 · Cited by 1,242 · see citing works
Innate immune memory in the brain shapes neurological disease hallmarks
Wendeln, A.-C., Degenhardt, K., Kaurani, L., Gertig, M., Ulas, T., Jain, G., Wagner, J., Häsler, L. M., Wild, K., Skodras, A., et al. (2018) · Nature · doi:10.1038/s41586-018-0023-4 · Cited by 956 · see citing works
Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., & Badylak, S. F. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.02.034 · Cited by 926 · see citing works
Sterile inflammation in the liver
Kubes, P., & Mehal, W. Z. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.09.008 · Cited by 666 · see citing works
Tumor-associated macrophages: Functional diversity, clinical significance, and open questions
Biswas, S. K., Allavena, P., & Mantovani, A. (2013) · Seminars in Immunopathology · doi:10.1007/s00281-013-0367-7 · Cited by 551 · see citing works
Self-citationImaging robust microglial activation after lipopolysaccharide administration in humans with PET
Sandiego, C. M., Gallezot, J.-D., Pittman, B., Nabulsi, N., Lim, K., Lin, S.-F., Matuskey, D., Lee, J.-Y., O’Connor, K. C., Huang, Y., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1511003112 · Cited by 356 · see citing works
Martínez-García, J. J., Martínez-Banaclocha, H., Angosto-Bazarra, D., de Torre-Minguela, C., Baroja-Mazo, A., Alarcón-Vila, C., Martínez-Alarcón, L., Amores-Iniesta, J., Martín-Sánchez, F., Ercole, G. A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10626-x · Cited by 233 · see citing works
Innate Immune Programing by Endotoxin and Its Pathological Consequences
Morris, M. C., Gilliam, E. A., & Li, L. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00680 · Cited by 224 · see citing works
Stress-induced neuroinflammation: role of the toll-like receptor-4 pathway
Gárate, I., Garcia-Bueno, B., Madrigal, J. L. M., Caso, J. R., Alou, L., Gomez-Lus, M. L., Micó, J. A., & Leza, J. C. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.07.005 · Cited by 202 · see citing works
Li, Y., Zhang, P., Wang, C., Han, C., Meng, J., Liu, X., Xu, S., Li, N., Wang, Q., Shi, X., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.454538 · Cited by 177 · see citing works
Kahn, M. S., Kranjac, D., Alonzo, C. A., Haase, J. H., Cedillos, R. O., McLinden, K. A., Boehm, G. W., & Chumley, M. J. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.01.010 · Cited by 177 · see citing works
Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways
Murray, P. J., & Smale, S. T. (2012) · Nature Immunology · doi:10.1038/ni.2391 · Cited by 170 · see citing works
Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages
Ding, X., Kambara, H., Guo, R., Kanneganti, A., Acosta-Zaldívar, M., Li, J., Liu, F., Bei, T., Qi, W., Xie, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27034-9 · Cited by 115 · see citing works
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., et al. (2011) · Shock · doi:10.1097/shk.0b013e318225ad7e · Cited by 106 · see citing works
miR-15a/16 Regulates Macrophage Phagocytosis after Bacterial Infection
Moon, H.-G., Yang, J., Zheng, Y., & Jin, Y. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401372 · Cited by 81 · see citing works
Zelkha, S. A., Freilich, R. W., & Amar, S. (2010) · Periodontology 2000 · doi:10.1111/j.1600-0757.2010.00358.x · Cited by 81 · see citing works
Noncoding RNAs regulate NF-κB signaling to modulate blood vessel inflammation
Cheng, H. S., Njock, M.-S., Khyzha, N., Dang, L. T., & Fish, J. E. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00422 · Cited by 69 · see citing works
Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease
Tan-Garcia, A., Wai, L.-E., Zheng, D., Ceccarello, E., Jo, J., Banu, N., Khakpoor, A., Chia, A., Tham, C. Y. L., Tan, A. T., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.04.023 · Cited by 68 · see citing works
Janelsins, B. M., Lu, M., & Datta, S. K. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311987111 · Cited by 56 · see citing works
Mullane, K., & Williams, M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.027 · Cited by 32 · see citing works
Perdiguero, E., Kharraz, Y., Serrano, A. L., & Muñoz-Cánoves, P. (2012) · Cell Cycle · doi:10.4161/cc.11.5.19374 · Cited by 30 · see citing works
Palmer, C. D., Romero-Tejeda, M., Sirignano, M., Sharma, S., Allen, T. M., Altfeld, M., & Jost, S. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501888 · Cited by 16 · see citing works
Hatton‐Jones, K. M., du Toit, E. F., & Cox, A. J. (2022) · Neurogastroenterology & Motility · doi:10.1111/nmo.14300 · Cited by 5 · see citing works
- Authors
- Biswas, S. K., & Lopez-Collazo, E.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Biswas, Subhra K.
- Venue
- Trends in Immunology
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 30
- Issue
- 10
- Pages
- 475-487
- ISSN
- 1471-4906 (ISSN-L)
- OpenAlex
- W1993197717
- Cited by
- 1,318
- References
- 6
- Citations by year
- 2026: 56 · 2025: 59 · 2024: 72 · 2023: 64 · 2022: 74 · 2021: 79 · 2020: 86 · 2019: 84 · 2018: 90 · 2017: 94 · 2016: 89 · 2015: 80 · 2014: 82 · 2013: 107 · 2012: 98
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- endotoxin tolerance, lipopolysaccharide, monocytes, macrophages, sepsis, immunosuppression, MyD88 signaling, TRIF signaling, NF-κB, chromatin modification, microRNA, innate immunity, inflammation regulation
- MeSH terms
- Animals, Chromatin, Endotoxins, Humans, Immune Tolerance, Lymphocytes, Macrophages, Monocytes, Signal Transduction, Apoptosis, Systemic Inflammatory Response Syndrome, Receptors, Chemokine, MicroRNAs, Toll-Like Receptors
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