Release of High Mobility Group Box 1 by Dendritic Cells Controls T Cell Activation via the Receptor for Advanced Glycation End Products
Open accessAbstract
High mobility group box 1 (HMGB1) is an abundant and conserved nuclear protein that is released by necrotic cells and acts in the extracellular environment as a primary proinflammatory signal. In this study we show that human dendritic cells, which are specialized in Ag presentation to T cells, actively release their own HMGB1 into the extracellular milieu upon activation. This secreted HMGB1 is necessary for the up-regulation of CD80, CD83, and CD86 surface markers of human dendritic cells and for IL-12 production. The HMGB1 secreted by dendritic cells is also required for the clonal expansion, survival, and functional polarization of naive T cells. Using neutralizing Abs and receptor for advanced glycation end product-deficient (RAGE−/−) cells, we demonstrate that RAGE is required for the effect of HMGB1 on dendritic cells. HMGB1/RAGE interaction results in downstream activation of MAPKs and NF-κB. The use of an ancient signal of necrosis, HMGB1, by dendritic cells to sustain their own maturation and for activation of T lymphocytes represents a profitable evolutionary mechanism.
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HMGB1-TLR4 ligation on DCs promotes antigen processing and cross-presentation but does not induce DC maturation, which is mainly stimulated by RAGE.
“In particular, the ligation of HGMB1 to TLR4 on DCs promotes antigen processing and cross-presentation, yet does not induce DC maturation, which is mainly stimulated by RAGE [870, 916].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [916]
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Cites
Dendritic cells and the control of immunity
Banchereau, J., & Steinman, R. M. (1998) · Nature · doi:10.1038/32588 · Cited by 14,244 · see citing works
A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A. J. (1997) · Nature · doi:10.1038/41131 · Cited by 6,137 · see citing works
Sallusto, F., & Lanzavecchia, A. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.4.1109 · Cited by 5,129 · see citing works
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002) · Nature · doi:10.1038/nature00858 · Cited by 4,221 · see citing works
Self-citationHMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Wang, H., Bloom, O., Zhang, M., Vishnubhakat, J. M., Ombrellino, M., Che, J., Frazier, A., Yang, H., Ivanova, S., Borovikova, L. V., et al. (1999) · Science · doi:10.1126/science.285.5425.248 · Cited by 3,386 · see citing works
Takeda, K., & Akira, S. (2004) · Seminars in Immunology · doi:10.1016/j.smim.2003.10.003 · Cited by 2,461 · see citing works
Mellman, I., & Steinman, R. M. (2001) · Cell · doi:10.1016/s0092-8674(01)00449-4 · Cited by 2,256 · see citing works
Park, J. S., Svetkauskaite, D., He, Q., Kim, J., Strassheim, D., Ishizaka, A., & Abraham, E. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306793200 · Cited by 1,560 · see citing works
Mueller, D. L., Jenkins, M. K., & Schwartz, R. H. (1989) · Annual Review of Immunology · doi:10.1146/annurev.iy.07.040189.002305 · Cited by 1,501 · see citing works
Andersson, U., Wang, H., Palmblad, K., Aveberger, A.-C., Bloom, O., Erlandsson-Harris, H., Janson, A., Kokkola, R., Zhang, M., Yang, H., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.4.565 · Cited by 1,401 · see citing works
Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion
Bonaldi, T., Talamo, F., Scaffidi, P., Ferrera, D., Porto, A., Bachi, A., Rubartelli, A., Agresti, A., & Bianchi, M. E. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg516 · Cited by 1,252 · see citing works
Self-citationThe Receptor for Advanced Glycation End Products (RAGE) Is a Cellular Binding Site for Amphoterin
Hori, O., Brett, J., Slattery, T., Cao, R., Zhang, J., Chen, J. X., Nagashima, M., Lundh, E. R., Vijay, S., Nitecki, D., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.43.25752 · Cited by 1,151 · see citing works
Reversing established sepsis with antagonists of endogenous high-mobility group box 1
Yang, H., Ochani, M., Li, J., Qiang, X., Tanovic, M., Harris, H. E., Susarla, S. M., Ulloa, L., Wang, H., DiRaimo, R., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2434651100 · Cited by 1,126 · see citing works
IDENTIFICATION OF A NOVEL CELL TYPE IN PERIPHERAL LYMPHOID ORGANS OF MICE
Steinman, R. M., Lustig, D. S., & Cohn, Z. A. (1974) · The Journal of Experimental Medicine · doi:10.1084/jem.139.6.1431 · Cited by 1,052 · see citing works
Regulation of T Cell Immunity by Dendritic Cells
Lanzavecchia, A., & Sallusto, F. (2001) · Cell · doi:10.1016/s0092-8674(01)00455-x · Cited by 997 · see citing works
MATURE T LYMPHOCYTE APOPTOSIS—Immune Regulation in a Dynamic and Unpredictable Antigenic Environment
Lenardo, M. J., Chan, F. K.-M., Hornung, F., McFarland, H. F., Siegel, R. M., Wang, J., & Zheng, L. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.221 · Cited by 931 · see citing works
Gardella, S., Andrei, C., Ferrera, D., Lotti, L. V., Torrisi, M. R., Bianchi, M. E., & Rubartelli, A. (2002) · EMBO Reports · doi:10.1093/embo-reports/kvf198 · Cited by 926 · see citing works
Self-citationDiabetes-Associated Sustained Activation of the Transcription Factor Nuclear Factor-κB
Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P. M., Chen, J., Hong, M., Luther, T., Henle, T., Klöting, I., et al. (2001) · Diabetes · doi:10.2337/diabetes.50.12.2792 · Cited by 826 · see citing works
Self-citationThe Toll receptor family and microbial recognition.
Medzhitov, R., & Janeway, C. (2000) · Trends in Microbiology · doi:10.1016/s0966-842x(00)01845-x · Cited by 739 · see citing works
Huttunen, H. J., Fages, C., & Rauvala, H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.19919 · Cited by 629 · see citing works
HMGB1 is an endogenous immune adjuvant released by necrotic cells
Rovere, P. Q., Capobianco, A., Scaffidi, P., Valentinis, B., Catalanotti, F., Giazzon, M., Dumitriu, I. E., Müller, S., Iannacone, M., Traversari, C., et al. (2004) · EMBO Reports · doi:10.1038/sj.embor.7400205 · Cited by 591 · see citing works
Self-citationThe Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins
Chavakis, T., Bierhaus, A., Al‐Fakhri, N., Schneider, D., Witte, S., Linn, T., Nagashima, M., Morser, J., Arnold, B., Preissner, K. T., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030800 · Cited by 583 · see citing works
Self-citationLiliensiek, B., Weigand, M. A., Bierhaus, A., Nicklas, W., Kasper, M. E., Hofer, S., Plachky, J., Gröne, H.-J., Kurschus, F. C., Schmidt, A. M., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18704 · Cited by 525 · see citing works
Self-citationSteinman, R. M., Kaplan, G., Witmer, M. D., & Cohn, Z. A. (1979) · The Journal of Experimental Medicine · doi:10.1084/jem.149.1.1 · Cited by 519 · see citing works
RAGE is the Major Receptor for the Proinflammatory Activity of HMGB1 in Rodent Macrophages
Kokkola, R., Andersson, Å., Mullins, G. E., Östberg, T., Treutiger, C.-J., Arnold, B., Nawroth, P. P., Andersson, J., Harris, R. A., & Harris, H. E. (2005) · Scandinavian Journal of Immunology · doi:10.1111/j.0300-9475.2005.01534.x · Cited by 496 · see citing works
Self-citationTransport of Peptide-MHC Class II Complexes in Developing Dendritic Cells
Turley, S. J., Inaba, K., Garrett, W. S., Ebersold, M. W., Unternaehrer, J., Steinman, R. M., & Mellman, I. (2000) · Science · doi:10.1126/science.288.5465.522 · Cited by 477 · see citing works
Liliensiek, B., Weigand, M. A., Bierhaus, A., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200418704 · Cited by 468 · see citing works
Messmer, D., Yang, H., Telusma, G., Knoll, F., Li, J., Messmer, B., Tracey, K. J., & Chiorazzi, N. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.1.307 · Cited by 447 · see citing works
Extracellular role of HMGB1 in inflammation and sepsis
Wang, H., Yang, H., & Tracey, K. J. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2003.01302.x · Cited by 439 · see citing works
Ardeshna, K. M., Pizzey, A. R., Devereux, S., & Khwaja, A. (2000) · Blood · doi:10.1182/blood.v96.3.1039 · Cited by 430 · see citing works
Mini‐review: The nuclear protein HMGB1 as a proinflammatory mediator
Harris, H. E., & Andersson, U. (2004) · European Journal of Immunology · doi:10.1002/eji.200424916 · Cited by 372 · see citing works
Müller, S., Ronfani, L., & Bianchi, M. E. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2003.01296.x · Cited by 368 · see citing works
Self-citationIFN-γ Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism
Rendon-Mitchell, B., Ochani, M., Li, J., Han, J., Wang, H., Yang, H., Susarla, S. M., Czura, C. J., Mitchell, R. A., Chen, G., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3890 · Cited by 337 · see citing works
Intestinal dendritic cells increase T cell expression of α4β7 integrin
Stagg, A. J., Kamm, M. A., & Knight, S. C. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200205)32:5 · Cited by 306 · see citing works
(2002) · PubMed · Cited by 292 · see citing works
Processing of engulfed apoptotic bodies yields T cell epitopes
Bellone, M., Iezzi, G., Rovere, P. Q., Galati, G., Ronchetti, A. B., Protti, M. P., Davoust, J. M., Rugarli, C., & Manfredi, A. A. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.159.11.5391 · Cited by 261 · see citing works
Self-citationDeath-defying immunity: do apoptotic cells influence antigen processing and presentation?
Albert, M. L. (2004) · Nature reviews. Immunology · doi:10.1038/nri11308 · Cited by 257 · see citing works
Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys
D’Amico, G., Frascaroli, G., Bianchi, G., Transidico, P., Doni, A., Vecchi, A., Sozzani, S., Allavena, P., & Mantovani, A. (2000) · Nature Immunology · doi:10.1038/80819 · Cited by 252 · see citing works
Sugaya, K., Fukagawa, T., Matsumoto, K., Mita, K., Takahashi, E., Ando, A., Inoko, H., & Ikemura, T. (1994) · Genomics · doi:10.1006/geno.1994.1517 · Cited by 242 · see citing works
HMGB1 is a potent trigger of arthritis
Andersson, J., & Erlandsson-Harris, H. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2003.01303.x · Cited by 169 · see citing works
Ball, T., Sperr, W. R., Valent, P., Lidholm, J., Spitzauer, S., Ebner, C., Kraft, D., & Valenta, R. (1999) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199906)29:06 · Cited by 141 · see citing works
Bianchi, M. E., & Manfredi, A. A. (2003) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/j.bbaexp.2003.10.017 · Cited by 123 · see citing works
Self-citationThermodynamics of HMGB1 Interaction with Duplex DNA
Müller, S., Bianchi, M. E., & Knapp, S. (2001) · Biochemistry · doi:10.1021/bi0100900 · Cited by 61 · see citing works
Self-citationBianchi, M. E. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.04.004 · Cited by 54 · see citing works
Self-citationHudson, B. I., Stickland, M. H., Grant, P. J., et al. (2001) · Diabetes · doi:10.2337/diabetes.50.12.2646 · Cited by 35 · see citing works
Kikuchi, K., Yanagawa, Y., Iwabuchi, K., et al. (2003) · Immunology Letters · doi:10.1016/s0165-2478(03)00134-2 · Cited by 31 · see citing works
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Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
How dying cells alert the immune system to danger
Kono, H., & Rock, K. L. (2008) · Nature Reviews Immunology · doi:10.1038/nri2215 · Cited by 1,737 · see citing works
HMGB1 is a therapeutic target for sterile inflammation and infection
Andersson, U., & Tracey, K. J. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101323 · Cited by 1,437 · see citing works
Tian, J., Avalos, A. M., Mao, S.-Y., Chen, B., Senthil, K., Wu, H., Parroche, P., Drabic, S., Golenbock, D., Sirois, C., et al. (2007) · Nature Immunology · doi:10.1038/ni1457 · Cited by 1,372 · see citing works
Role of advanced glycation end products in cellular signaling
Ott, C., Jacobs, K., Haucke, E., Navarrete Santos, A., Grune, T., & Simm, A. (2014) · Redox Biology · doi:10.1016/j.redox.2013.12.016 · Cited by 1,150 · see citing works
Kang, R., Chen, R., Zhang, Q., Hou, W., Wu, S., Cao, L., Huang, J., Yu, Y., Fan, X.-G., Yan, Z., et al. (2014) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2014.05.001 · Cited by 956 · see citing works
HMGB1: Endogenous Danger Signaling
Klune, J. R., Dhupar, R., Cardinal, J., Billiar, T. R., & Tsung, A. (2008) · Molecular Medicine · doi:10.2119/2008-00034.klune · Cited by 762 · see citing works
Kazama, H., Ricci, J.-E., Herndon, J. M., Hoppe, G., Green, D. R., & Ferguson, T. A. (2008) · Immunity · doi:10.1016/j.immuni.2008.05.013 · Cited by 627 · see citing works
High‐mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity
Bianchi, M. E., & Manfredi, A. A. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00574.x · Cited by 600 · see citing works
Self-citationHMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins
Bertheloot, D., & Latz, E. (2017) · Cellular & Molecular Immunology · doi:10.1038/cmi.2016.34 · Cited by 455 · see citing works
The RAGE axis: A fundamental mechanism signaling danger to the vulnerable vasculature
Yan, S. F., Ramasamy, R., & Schmidt, A. M. (2010) · Circulation Research · doi:10.1161/circresaha.109.212217 · Cited by 381 · see citing works
Masquerader: High Mobility Group Box-1 and Cancer
Ellerman, J. E., Brown, C. K., de Vera, M., Zeh, H. J., Billiar, T., Rubartelli, A., & Lotze, M. T. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1953 · Cited by 355 · see citing works
Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1
Tang, D., Shi, Y., Kang, R., Li, T., Xiao, W., Wang, H., & Xiao, X. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0806540 · Cited by 312 · see citing works
Engineering nanomedicines through boosting immunogenic cell death for improved cancer immunotherapy
Gao, J., Wang, W.-Q., Pei, Q., Lord, M. S., & Yu, H.-J. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-0400-z · Cited by 203 · see citing works
Regulation of osteoclast function and bone mass by RAGE
Zhou, Z., Immel, D., Xi, C.-X., Bierhaus, A., Feng, X., Mei, L., Nawroth, P., Stern, D. M., & Xiong, W.-C. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051947 · Cited by 178 · see citing works
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Zhou, Z., Han, J.-Y., Xi, C.-X., Xie, J.-X., Feng, X., Wang, C.-Y., Mei, L., & Xiong, W.-C. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.080234 · Cited by 160 · see citing works
Zou, J., Kawai, T., Tsuchida, T., Kozaki, T., Tanaka, H., Shin, K.-S., Kumar, H., & Akira, S. (2013) · Immunity · doi:10.1016/j.immuni.2012.12.007 · Cited by 103 · see citing works
HMGB1 is a bone‐active cytokine
Yang, J., Shah, R., Robling, A. G., Templeton, E., Yang, H., Tracey, K. J., & Bidwell, J. P. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21268 · Cited by 97 · see citing works
HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion
Su, Z., Sun, C., Zhou, C., Liu, Y., Zhu, H., Sandoghchian, S., Zheng, D., Peng, T., Zhang, Y., Jiao, Z., et al. (2011) · European Journal of Immunology · doi:10.1002/eji.201141879 · Cited by 81 · see citing works
- Authors
- Dumitriu, I. E., Baruah, P., Valentinis, B., Voll, R. E., Herrmann, M., Nawroth, P. P., Arnold, B., Bianchi, M. E., Manfredi, A. A., & Rovere-Querini, P.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- MolMed (Italy) (IT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Department of Internal Medicine III, Institute for Clinical Immunology and Rheumatology, Friedrich Alexander University , Erlangen-Nuremberg ,
- Heidelberg University (DE)
- German Cancer Research Center (DE)
- Vita-Salute San Raffaele University (IT)
- Cancer Immunotherapy and Gene Therapy Program, Clinical Immunology Unit, H. San Raffaele Scientific Institute , Milan ,
- Corresponding author
- Baruah, Paramita
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-06
- Volume
- 174
- Issue
- 12
- Pages
- 7506-7515
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2143998429
- Cited by
- 503
- References
- 46
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 11 · 2023: 12 · 2022: 24 · 2021: 16 · 2020: 22 · 2019: 16 · 2018: 19 · 2017: 30 · 2016: 29 · 2015: 32 · 2014: 29 · 2013: 39 · 2012: 29
- FWCI
- 22.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- HMGB1, dendritic cells, RAGE, T cell activation, dendritic cell maturation, IL-12, CD80, CD83, CD86, T cell polarization, necrosis, MAPK signaling, NF-κB, extracellular HMGB1
- MeSH terms
- Receptor for Advanced Glycation End Products, Cell Differentiation, Cell Survival, Cells, Cultured, Clone Cells, Cytosol, Dendritic Cells, Extracellular Space, Growth Inhibitors, Humans, Immune Sera, Lymphocyte Activation, Receptors, Immunologic, CD4-Positive T-Lymphocytes, T-Lymphocyte Subsets, Resting Phase, Cell Cycle, NF-kappa B, Th1 Cells, Interleukin-12, Coculture Techniques, Active Transport, Cell Nucleus, HMGB1 Protein, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Cell Proliferation
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