Gene-specific control of inflammation by TLR-induced chromatin modifications
Abstract
Toll-like receptors (TLRs) induce a multi-component inflammatory response that must be tightly regulated to avoid tissue damage. Most known regulatory mechanisms target TLR signalling pathways and thus broadly inhibit multiple aspects of the inflammatory response. Given the functional diversity of TLR-induced genes, we proposed that additional, gene-specific regulatory mechanisms exist to allow individual aspects of the TLR-induced response to be differentially regulated. Using an in vitro system of lipopolysaccharide tolerance in murine macrophages, we show that TLR-induced genes fall into two categories on the basis of their functions and regulatory requirements. We demonstrate that representatives from the two classes acquire distinct patterns of TLR-induced chromatin modifications. These gene-specific chromatin modifications are associated with transient silencing of one class of genes, which includes pro-inflammatory mediators, and priming of the second class, which includes antimicrobial effectors. These findings illustrate an adaptive response in macrophages and reveal component-specific regulation of inflammation.
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 [18]
Cites
Negative regulation of Toll-like receptor-mediated immune responses
Liew, F. Y., Xu, D., Brint, E. K., & O'Neill, L. A. J. (2005) · Nature Reviews Immunology · doi:10.1038/nri1630 · Cited by 1,509 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Pattern Recognition Receptors and Inflammation
Takeuchi, O., & Akira, S. (2010) · Cell · doi:10.1016/j.cell.2010.01.022 · Cited by 8,895 · see citing works
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
Trained immunity: A program of innate immune memory in health and– disease
Netea, M. G., Joosten, L. A. B., Latz, E., Mills, K. H. G., Natoli, G., Stunnenberg, H. G., O’Neill, L. A. J., & Xavier, R. J. (2016) · Science · doi:10.1126/science.aaf1098 · Cited by 2,768 · see citing works
The molecular hallmarks of epigenetic control
Allis, C. D., & Jenuwein, T. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.59 · Cited by 2,809 · see citing works
Defining trained immunity and its role in health and disease
Netea, M. G., Domínguez-Andrés, J., Barreiro, L. B., Chavakis, T., Divangahi, M., Fuchs, E., Joosten, L. A. B., van der Meer, J. W. M., Mhlanga, M. M., Mulder, W. J. M., et al. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0285-6 · Cited by 2,690 · 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
Toll-like Receptors and the Control of Immunity
Fitzgerald, K. A., & Kagan, J. C. (2020) · Cell · doi:10.1016/j.cell.2020.02.041 · Cited by 2,168 · see citing works
NF-κB, Inflammation, and Metabolic Disease
Baker, R. G., Hayden, M. S., & Ghosh, S. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2010.12.008 · Cited by 1,952 · 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
Disease Tolerance as a Defense Strategy
Medzhitov, R., Schneider, D. S., & Soares, M. P. (2012) · Science · doi:10.1126/science.1214935 · Cited by 1,718 · see citing works
Self-citationQuintin, J., Saeed, S., Martens, J. H. A., Giamarellos-Bourboulis, E. J., Ifrim, D. C., Logie, C., Jacobs, L., Jansen, T., Kullberg, B.-J., Wijmenga, C., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.06.006 · Cited by 1,289 · see citing works
Why does COVID-19 disproportionately affect older people?
Mueller, A. L., McNamara, M. S., & Sinclair, D. A. (2020) · Aging · doi:10.18632/aging.103344 · Cited by 1,128 · see citing works
Macrophage death and defective inflammation resolution in atherosclerosis
Tabas, I. (2010) · Nature Reviews Immunology · doi:10.1038/nri2675 · Cited by 1,120 · see citing works
Kawahara, T. L. A., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C. L., Boxer, L. D., Chang, H. Y., et al. (2009) · Cell · doi:10.1016/j.cell.2008.10.052 · Cited by 1,090 · 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
Schneider, D. S., & Ayres, J. S. (2008) · Nature Reviews Immunology · doi:10.1038/nri2432 · Cited by 783 · see citing works
Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6
Zhang, Q., Zhao, K., Shen, Q., Han, Y., Gu, Y., Li, X., Zhao, D., Liu, Y., Wang, C., Zhang, X., et al. (2015) · Nature · doi:10.1038/nature15252 · Cited by 807 · see citing works
Histone deacetylases as regulators of inflammation and immunity
Shakespear, M. R., Halili, M. A., Irvine, K. M., Fairlie, D. P., & Sweet, M. J. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.04.001 · Cited by 546 · see citing works
Ganal, S. C., Sanos, S. L., Kallfass, C., Oberle, K., Johner, C., Kirschning, C., Lienenklaus, S., Weiss, S., Staeheli, P., Aichele, P., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.05.020 · Cited by 484 · see citing works
The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance
Villagra, A., Cheng, F., Wang, H.-W., Suarez, I., Glozak, M., Maurin, M., Nguyen, D., Wright, K. L., Atadja, P. W., Bhalla, K., et al. (2009) · Nature Immunology · doi:10.1038/ni.1673 · Cited by 455 · see citing works
Disease tolerance and immunity in host protection against infection
Soares, M. P., Teixeira, L., & Moita, L. F. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2016.136 · Cited by 376 · see citing works
Epigenetic regulation of the innate immune response to infection
Zhang, Q., & Cao, X. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0151-6 · Cited by 366 · see citing works
Redox control of inflammation in macrophages
Brüne, B., Dehne, N., Grossmann, N., Jung, M., Namgaladze, D., Schmid, T., von Knethen, A., & Weigert, A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4785 · Cited by 377 · see citing works
Qiao, Y., Giannopoulou, E. G., Chan, C. H., Park, S.-H., Gong, S., Chen, J., Hu, X., Elemento, O., & Ivashkiv, L. B. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.009 · Cited by 330 · see citing works
Hu, X., Chakravarty, S. D., & Ivashkiv, L. B. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00707.x · Cited by 303 · see citing works
Beck, I. M. E., Vanden Berghe, W., Vermeulen, L., Yamamoto, K. R., Haegeman, G., & De Bosscher, K. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0013 · Cited by 298 · see citing works
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 · see citing works
Inflammation, Glutamate, and Glia in Depression:<i>A Literature Review</i>
McNally, L., Bhagwagar, Z., & Hannestad, J. (2008) · CNS Spectrums · doi:10.1017/s1092852900016734 · Cited by 289 · see citing works
Immune senescence, epigenetics and autoimmunity
Ray, D., & Yung, R. (2018) · Clinical Immunology · doi:10.1016/j.clim.2018.04.002 · Cited by 219 · see citing works
Pascual, M., Baliño, P., Alfonso-Loeches, S., Aragón, C. M. G., & Guerri, C. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.02.012 · Cited by 213 · see citing works
Functional diversity of microglia – how heterogeneous are they to begin with?
Hanisch, U.-K. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00065 · Cited by 195 · see citing works
Qualls, 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 · 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
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
Role of Epigenetics in Inflammation-Associated diseases
Shanmugam, M. K., & Sethi, G. (2013) · Subcellular Biochemistry · doi:10.1007/978-94-007-4525-4_27 · Cited by 141 · see citing works
Mylonas, K. J., Nair, M. G., Prieto-Lafuente, L., Paape, D., & Allen, J. E. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803463 · Cited by 140 · see citing works
Epigenetic Changes in Diabetes and Cardiovascular Risk
Keating, S. T., Plutzky, J., & El-Osta, A. (2016) · Circulation Research · doi:10.1161/circresaha.116.306819 · Cited by 139 · see citing works
Cheng, F., Lienlaf, M., Perez-Villarroel, P., Wang, H.-W., Lee, C., Woan, K., Woods, D., Knox, T., Bergman, J., Pinilla-Ibarz, J., et al. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2014.02.019 · Cited by 140 · see citing works
The gut microbiota and mucosal homeostasis: Colonized at birth or at adulthood, does it matter?
El Aidy, S., Hooiveld, G., Tremaroli, V., Bäckhed, F., & Kleerebezem, M. (2013) · Gut Microbes · doi:10.4161/gmic.23362 · Cited by 131 · see citing works
Stimulated Innate Resistance of Lung Epithelium Protects Mice Broadly against Bacteria and Fungi
Evans, S. E., Scott, B. L., Clement, C. G., Larson, D. T., Kontoyiannis, D., Lewis, R. E., LaSala, P. R., Pawlik, J., Peterson, J. W., Chopra, A. K., et al. (2010) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2008-0260oc · Cited by 129 · see citing works
Sex differences in neuroinflammation and neuroprotection in ischemic stroke
Spychala, M. S., Honarpisheh, P., & McCullough, L. D. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.23962 · Cited by 127 · see citing works
Huggins, M. A., Sjaastad, F. V., Pierson, M., Kucaba, T. A., Swanson, W., Staley, C., Weingarden, A. R., Jensen, I. J., Danahy, D. B., Badovinac, V. P., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.028 · Cited by 114 · see citing works
Cheng, F., Lienlaf, M., Wang, H.-W., Perez-Villarroel, P., Lee, C., Woan, K., Rock-Klotz, J., Sahakian, E., Woods, D., Pinilla-Ibarz, J., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302778 · Cited by 106 · see citing works
IKKα Causes Chromatin Modification on Pro-Inflammatory Genes by Cigarette Smoke in Mouse Lung
Yang, S.-R., Valvo, S., Yao, H., Kode, A., Rajendrasozhan, S., Edirisinghe, I., Caito, S., Adenuga, D., Henry, R., Fromm, G., et al. (2008) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2007-0379oc · Cited by 98 · see citing works
Myeloid cell dysfunction and the pathogenesis of the diabetic chronic wound
Wicks, K., Torbica, T., & Mace, K. A. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.04.006 · Cited by 93 · see citing works
Jung, M., Ören, B., Mora, J., Mertens, C., Dziumbla, S., Popp, R., Weigert, A., Grossmann, N., Fleming, I., & Brüne, B. (2016) · Science Signaling · doi:10.1126/scisignal.aaf3241 · Cited by 87 · see citing works
Wang, A., Pope, S. D., Weinstein, J. S., Yu, S., Zhang, C., Booth, C. J., & Medzhitov, R. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820704116 · Cited by 67 · see citing works
Self-citationEpigenetic Mechanisms Governing Innate Inflammatory Responses
Perkins, D. J., Patel, M. C., Blanco, J. C. G., & Vogel, S. N. (2016) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2016.0003 · Cited by 51 · see citing works
Therapeutic Cancer Vaccines—T Cell Responses and Epigenetic Modulation
Kartikasari, A. E. R., Prakash, M. D., Cox, M., Wilson, K., Boer, J. C., Cauchi, J. A., & Plebanski, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03109 · Cited by 54 · see citing works
The intersect of genetics, environment, and microbiota in asthma-perspectives and challenges
Tang, H. H. F., Teo, S. M., Sly, P. D., Holt, P. G., & Inouye, M. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.08.026 · Cited by 43 · see citing works
Benjaskulluecha, S., Boonmee, A., Pattarakankul, T., Wongprom, B., Klomsing, J., & Palaga, T. (2022) · Scientific Reports · doi:10.1038/s41598-022-05929-x · Cited by 34 · see citing works
APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses
Friday, C. M., Stephens, I. O., Smith, C. T., Lee, S., Satish, D., Devanney, N. A., Cohen, S., Morganti, J. M., Gordon, S. M., & Johnson, L. A. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106983 · Cited by 33 · see citing works
Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target
Yan, C., Koda, S., Wu, J., Zhang, B., Yu, Q., Netea, M. G., Tang, R., & Zheng, K. (2020) · Hepatology · doi:10.1002/hep.31395 · Cited by 21 · see citing works
Epigenetic preparation of future gene induction kinetics
Xiong, J., & Zhu, B. (2025) · Annual Review of Genetics · doi:10.1146/annurev-genet-012825-093148 · Cited by 12 · see citing works
- Authors
- Foster, S. L., Hargreaves, D. C., & Medzhitov, R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Medzhitov, Ruslan
- Venue
- Nature
- Published
- 2007-05-30
- Volume
- 447
- Issue
- 7147
- Pages
- 972-978
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2041308303
- Cited by
- 1,344
- References
- 1
- Citations by year
- 2026: 63 · 2025: 81 · 2024: 73 · 2023: 69 · 2022: 75 · 2021: 96 · 2020: 86 · 2019: 75 · 2018: 75 · 2017: 50 · 2016: 80 · 2015: 60 · 2014: 78 · 2013: 71 · 2012: 57
- FWCI
- 23.69
- Type
- journal article
- Language
- en
- Update notices
- erratum (2008-01-03)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- Toll-like receptors, chromatin modification, gene-specific regulation, inflammation, lipopolysaccharide tolerance, macrophages, gene silencing, transcriptional priming, pro-inflammatory mediators, adaptive immunity
- MeSH terms
- Animals, Cells, Cultured, Chromatin, Gene Expression Regulation, Histones, Inflammation, Lipopolysaccharides, Macrophages, Models, Genetic, Promoter Regions, Genetic, Transcription, Genetic, Chromatin Assembly and Disassembly, Toll-Like Receptor 4, Mice
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
