HMGB1 SIGNALS THROUGH TOLL-LIKE RECEPTOR (TLR) 4 AND TLR2
Abstract
In response to bacterial endotoxin (e.g., LPS) or endogenous proinflammatory cytokines (e.g., TNF and IL-1beta), innate immune cells release HMGB1, a late cytokine mediator of lethal endotoxemia and sepsis. The delayed kinetics of HMGB1 release makes it an attractive therapeutic target with a wider window of opportunity for the treatment of lethal systemic inflammation. However, the receptor(s) responsible for HMGB1-mediated production of proinflammatory cytokines has not been well characterized. Here we demonstrate that in human whole blood, neutralizing antibodies against Toll-like receptor 4 (TLR4, but not TLR2 or receptor for advanced glycation end product) dose-dependently attenuate HMGB1-induced IL-8 release. Similarly, in primary human macrophages, HMGB1-induced TNF release is dose-dependently inhibited by anti-TLR4 antibodies. In primary macrophages from knockout mice, HMGB1 activates significantly less TNF release in cells obtained from MyD88 and TLR4 knockout mice as compared with cells from TLR2 knockout and wild-type controls. However, in human embryonic kidney 293 cells transfected with TLR2 or TLR4, HMGB1 effectively induces IL-8 release only from TLR2 overexpressing cells. Consistently, anti-TLR2 antibodies dose-dependently attenuate HMGB1-induced IL-8 release in human embryonic kidney/TLR2-expressing cells and markedly reduce HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells. Taken together, our data suggest that there is a differential usage of TLR2 and TLR4 in HMGB1 signaling in primary cells and in established cell lines, adding complexity to studies of HMGB1 signaling which was not previously expected.
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Several purified endogenous molecules, including HSPs, HMGB1 and uric acid, can induce the production of pro-inflammatory cytokines through TLR2 and/or TLR4 in vitro.
“Although several of the purified endogenous molecules, including HSPs, HMGb1 and uric acid, can induce the production of pro-inflammatory cytokines through TLR2 and/or TLR4 in vitro25–27, the relevance of these observations has previously been questioned because of the possibility of microbial contamination: several of these proteins, including HSPs and HMGb1, bind lipopolysaccharide (LPS), making”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [26]
Cites
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
HMG-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
Self-citationToll-like receptors in the induction of the innate immune response
Aderem, A. A., & Ulevitch, R. J. (2000) · Nature · doi:10.1038/35021228 · Cited by 3,047 · see citing works
Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia
Tracey, K. J., Fong, Y., Hesse, D. G., Manogue, K. R., Lee, A. T., Kuo, G. C., Lowry, S. F., & Cerami, A. (1987) · Nature · doi:10.1038/330662a0 · Cited by 2,448 · see citing works
Self-citationPark, 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
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
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
Self-citationThe nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion
Tsung, A., Sahai, R., Tanaka, H., Nakao, A., Fink, M. P., Lotze, M. T., Yang, H., Li, J., Tracey, K. J., Geller, D. A., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20042614 · Cited by 1,113 · see citing works
Self-citationHSP70 as Endogenous Stimulus of the Toll/Interleukin-1 Receptor Signal Pathway
Vabulas, R. M., Ahmad‐Nejad, P., Ghose, S., Kirschning, C. J., Issels, R. D., & Wagner, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111204200 · Cited by 949 · see citing works
High mobility group box 1 protein interacts with multiple Toll-like receptors
Park, J. S., Gamboni-Robertson, F., He, Q., Svetkauskaite, D., Kim, J., Strassheim, D., Sohn, J.-W., Yamada, S., Maruyama, I., Banerjee, A. M., et al. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00401.2005 · Cited by 934 · see citing works
Cutting Edge: HMG-1 as a Mediator of Acute Lung Inflammation
Abraham, E. H., Arcaroli, J. J., Carmody, A., Wang, H., & Tracey, K. J. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.6.2950 · Cited by 692 · see citing works
Self-citationThe cytokine activity of HMGB1
Yang, H., Wang, H., Czura, C. J., & Tracey, K. J. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.1104648 · Cited by 545 · see citing works
Self-citationToll-like receptors; their physiological role and signal transduction system.
Takeuchi, O., & Akira, S. (2001) · International Immunopharmacology · doi:10.1016/s1567-5769(01)00010-8 · Cited by 506 · see citing works
Bowie, A., & O'Neill, L. A. J. (2000) · Journal of Leukocyte Biology · doi:10.1002/jlb.67.4.508 · Cited by 495 · see citing works
Taniguchi, N., Kawahara, K.-I., Yone, K., Hashiguchi, T., Yamakuchi, M., Goto, M., Inoue, K., Yamada, S., Ijiri, K., Matsunaga, S., et al. (2003) · Arthritis & Rheumatism · doi:10.1002/art.10859 · Cited by 482 · see citing works
Degryse, B., Bonaldi, T., Scaffidi, P., Müller, S., Resnati, M., Sanvito, F., Arrigoni, G., & Bianchi, M. E. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.152.6.1197 · Cited by 451 · see citing works
Latz, E., Visintin, A., Lien, E., Fitzgerald, K. A., Monks, B. G., Kurt‐Jones, E. A., Golenbock, D. T., & Espevik, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207873200 · Cited by 448 · see citing works
Self-citationSummary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family
Martin, M. U., & Wesche, H. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(02)00320-8 · Cited by 426 · see citing works
Kokkola, R., Li, J., Sundberg, E., Aveberger, A.-C., Palmblad, K., Yang, H., Tracey, K. J., Andersson, J., & Harris, H. E. (2003) · Arthritis & Rheumatism · doi:10.1002/art.11161 · Cited by 325 · see citing works
Self-citationSappington, P. L., Yang, R., Yang, H., Tracey, K. J., Delude, R. L., & Fink, M. P. (2002) · Gastroenterology · doi:10.1053/gast.2002.35391 · Cited by 319 · see citing works
Self-citation(2002) · PubMed · Cited by 292 · see citing works
High mobility group box chromosomal protein 1: A novel proinflammatory mediator in synovitis
Kokkola, R., Sundberg, E., Ulfgren, A. ‐., Palmblad, K., Li, J., Wang, H., Ulloa, L., Yang, H., Yan, X. ‐., Furie, R., et al. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10540 · Cited by 290 · see citing works
Self-citationSignal Transduction Pathways Activated by the IL-1 Receptor/Toll-Like Receptor Superfamily
O'Neill, L. A. J. (2002) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-59430-4_3 · Cited by 282 · see citing works
Joosten, L. A. B., Koenders, M. I., Smeets, R. L., Heuvelmans‐Jacobs, M., Helsen, M. M. A., Takeda, K., Akira, S., Lubberts, E., van de Loo, F. A. J., & van den Berg, W. B. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.11.6145 · Cited by 216 · see citing works
Amphoterin as an extracellular regulator of cell motility: from discovery to disease
Huttunen, H. J., & Rauvala, H. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2003.01301.x · Cited by 173 · see citing works
Agnello, D., Wang, H., Yang, H., Tracey, K. J., & Ghezzi, P. (2002) · Cytokine · doi:10.1006/cyto.2002.0890 · Cited by 148 · see citing works
Self-citationShi, S., Nathan, C., Schnappinger, D., Drenkow, J., Fuortes, M., Block, E. F., Ding, A. H., Gingeras, T., Schoolnik, G. K., Akira, S., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030603 · Cited by 146 · see citing works
Self-citationRecombinant HMGB1 with cytokine-stimulating activity.
Li, J.-H., Wang, H., Mason, J. M., Levine, J., Yu, M., Ulloa, L., Czura, C., Tracey, K., & Yang, H. (2004) · JIM - Journal of Immunological Methods · doi:10.1016/j.jim.2004.04.019 · Cited by 142 · see citing works
Self-citationDelude, R. L., Yoshimura, A., Ingalls, R. R., et al. (1998) · PubMed · Cited by 92 · see citing works
Delude, R. L., Yoshimura, A., Ingalls, R. R., et al. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.6.3001 · Cited by 85 · see citing works
Yoshimura, A., Lien, E., Ingalls, R., Tuomanen, E., Dziarski, R., & Golenbock, D. (1999) · Journal of Immunology · doi:10.4049/jimmunol.163.1.1 · Cited by 2 · see citing works
Self-citation
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Cited by
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Sterile inflammation: sensing and reacting to damage
Chen, G. Y., & Nuñez, G. (2010) · Nature Reviews Immunology · doi:10.1038/nri2873 · Cited by 3,051 · 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
Self-citationChen, C.-J., Kono, H., Golenbock, D., Reed, G., Akira, S., & Rock, K. L. (2007) · Nature Medicine · doi:10.1038/nm1603 · Cited by 876 · see citing works
Self-citationConsensus guidelines for the detection of immunogenic cell death
Kepp, O., Senovilla, L., Vitale, I., Vacchelli, E., Adjemian, S., Agostinis, P., Apetoh, L., Aranda, F., Barnaba, V., Bloy, N., et al. (2014) · OncoImmunology · doi:10.4161/21624011.2014.955691 · Cited by 832 · see citing works
Self-citationNecrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome
Iyer, S. S., Pulskens, W. P., Sadler, J. J., Butter, L. M., Teske, G. J., Ulland, T. K., Eisenbarth, S. C., Florquin, S., Flavell, R. A., Leemans, J. C., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908698106 · Cited by 691 · see citing works
Hypertension-Linked Pathophysiological Alterations in the Gut
Santisteban, M. M., Qi, Y., Zubcevic, J., Kim, S., Yang, T., Shenoy, V., Cole-Jeffrey, C. T., Lobaton, G. O., Stewart, D. C., Rubiano, A., et al. (2017) · Circulation Research · doi:10.1161/circresaha.116.309006 · Cited by 525 · see citing works
Pattern recognition receptors and central nervous system repair
Kigerl, K. A., de Rivero Vaccari, J. P., Dietrich, W. D., Popovich, P. G., & Keane, R. W. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.01.001 · Cited by 490 · see citing works
Uric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis
Gasse, P., Riteau, N., Charron, S., Girre, S., Fick, L., Pétrilli, V., Tschopp, J., Lagente, V., Quesniaux, V. F. J., Ryffel, B., et al. (2009) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200808-1274oc · Cited by 410 · see citing works
Targeting HMGB1 in inflammation
Yang, H., & Tracey, K. J. (2010) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2009.11.019 · Cited by 351 · see citing works
Self-citationDAMPs as mediators of sterile inflammation in aging-related pathologies
Feldman, N., Rotter-Maskowitz, A., & Okun, E. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.01.003 · Cited by 283 · see citing works
Eigenbrod, T., Park, J.-H., Harder, J., Iwakura, Y., & Núñez, G. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.12.8194 · Cited by 228 · see citing works
High‐mobility group box‐1 in sterile inflammation
Tsung, A., Tohme, S., & Billiar, T. R. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12276 · Cited by 187 · see citing works
Toll-like Receptors in Defense and Damage of the Central Nervous System
Aravalli, R. N., Peterson, P. K., & Lokensgard, J. R. (2007) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-007-9071-5 · Cited by 173 · see citing works
Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury
Leaf, I. A., Nakagawa, S., Johnson, B. G., Cha, J. J., Mittelsteadt, K., Guckian, K. M., Gomez, I. G., Altemeier, W. A., & Duffield, J. S. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87532 · Cited by 151 · see citing works
The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming
Fonken, L. K., Frank, M. G., Kitt, M. M., D'Angelo, H. M., Norden, D. M., Weber, M. D., Barrientos, R. M., Godbout, J. P., Watkins, L. R., & Maier, S. F. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1161-16.2016 · Cited by 139 · see citing works
Haj-Mirzaian, A., Amiri, S., Amini-Khoei, H., Hosseini, M.-J., Haj-Mirzaian, A., Momeny, M., Rahimi-Balaei, M., & Dehpour, A. R. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.10.023 · Cited by 100 · 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
Self-citationHolmlund, U., Wähämaa, H., Bachmayer, N., Bremme, K., Sverremark‐Ekström, E., & Palmblad, K. (2007) · Immunology · doi:10.1111/j.1365-2567.2007.02662.x · Cited by 83 · see citing works
Miguel, C. A., Noya-Riobó, M. V., Mazzone, G. L., Villar, M. J., & Coronel, M. F. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105188 · Cited by 70 · see citing works
Cheng, M., Liu, H., Zhang, D., Liu, Y., Wang, C., Liu, F., & Chen, J. (2015) · American Journal of Nephrology · doi:10.1159/000381464 · Cited by 66 · see citing works
Luan, Z.-G., Zhang, X.-J., Yin, X.-H., Ma, X.-C., Zhang, H., Zhang, C., & Guo, R.-X. (2013) · Immunobiology · doi:10.1016/j.imbio.2013.04.013 · Cited by 59 · see citing works
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Yang, Q.-W. (2010) · Frontiers in Bioscience · doi:10.2741/s119 · Cited by 55 · see citing works
Wang, J.-S., Sheu, W. H.-H., Lee, W.-J., Lee, I.-T., Lin, S.-Y., Lee, W.-L., Liang, K.-W., & Lin, S.-J. (2018) · Clinica Chimica Acta · doi:10.1016/j.cca.2018.04.032 · Cited by 5 · see citing works
- Authors
- Yu, M., Wang, H., Ding, A., Golenbock, D. T., Latz, E., Czura, C. J., Fenton, M. J., Tracey, K. J., & Yang, H.
- Affiliations
- Feinstein Institute for Medical Research (US)
- Cornell University (US)
- University of Massachusetts Chan Medical School (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Yu, Man
- Wang, Haichao
- Czura, Christopher J.
- Tracey, Kevin J.
- Yang, Huan
- ORCID
- Venue
- Shock
- Published
- 2006-08
- Volume
- 26
- Issue
- 2
- Pages
- 174-179
- ISSN
- 1073-2322 (ISSN-L)
- OpenAlex
- W2021736304
- Cited by
- 832
- References
- 32
- Citations by year
- 2026: 20 · 2025: 20 · 2024: 26 · 2023: 35 · 2022: 35 · 2021: 40 · 2020: 40 · 2019: 28 · 2018: 42 · 2017: 48 · 2016: 55 · 2015: 53 · 2014: 59 · 2013: 48 · 2012: 62
- FWCI
- 16.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Shock (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM062508)
- National Center for Research Resources (M01RR018535)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- HMGB1, TLR4, TLR2, HMGB1 signaling, IL-8 release, TNF release, macrophages, MyD88, sepsis, endotoxemia, systemic inflammation, receptor for advanced glycation end products
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Antibodies, Monoclonal, Blood Cells, Cell Line, Cricetulus, Dose-Response Relationship, Drug, Dose-Response Relationship, Immunologic, Cricetinae, Humans, Receptors, Immunologic, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-8, CHO Cells, Glycation End Products, Advanced, Mice, Knockout, HMGB1 Protein, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice
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