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Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

Nature volume 418, pages 191–195 (2002)Cite this article

A Corrigendum to this article was published on 30 September 2010

Abstract

High mobility group 1 (HMGB1) protein is both a nuclear factor and a secreted protein. In the cell nucleus it acts as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets1,2. Outside the cell, it binds with high affinity to RAGE (the receptor for advanced glycation end products)3 and is a potent mediator of inflammation4,5,6. HMGB1 is secreted by activated monocytes and macrophages4, and is passively released by necrotic or damaged cells7,8,9. Here we report that Hmgb1-/- necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours. Apoptotic cells do not release HMGB1 even after undergoing secondary necrosis and partial autolysis, and thus fail to promote inflammation even if not cleared promptly by phagocytic cells. In apoptotic cells, HMGB1 is bound firmly to chromatin because of generalized underacetylation of histone and is released in the extracellular medium (promoting inflammation) if chromatin deacetylation is prevented. Thus, cells undergoing apoptosis are programmed to withhold the signal that is broadcast by cells that have been damaged or killed by trauma.

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Figure 1: Chromatin association of HMGB1 in living and dead HeLa cells.
Figure 2: HMGB1 dynamics in living and apoptotic cells.
Figure 3: Chromatin changes that occur in apoptosis create binding substrates for HMGB1.
Figure 4: HMGB1 release promotes inflammatory responses.

References

  1. Bustin, M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol. Cell. Biol. 19, 5237–5246 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bianchi, M. E. & Beltrame, M. Upwardly mobile proteins. The role of HMG proteins in chromatin structure, gene expression and neoplasia. EMBO Rep. 1, 109–114 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hori, O. et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. J. Biol. Chem. 270, 25752–25761 (1995)

    Article  CAS  PubMed  Google Scholar 

  4. Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999)

    Article  CAS  PubMed  Google Scholar 

  5. Abraham, E., Arcaroli, J., Carmody, A., Wang, H. & Tracey, K. J. HMG-1 as a mediator of acute lung inflammation. J. Immunol. 165, 2950–2954 (2000)

    Article  CAS  PubMed  Google Scholar 

  6. Andersson, U. et al. High Mobility Group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Degryse, B. et al. The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J. Cell Biol. 152, 1197–2006 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Müller, S. et al. The double life of HMGB1 chromatin protein: architectural factor and extracellular signal. EMBO J. 16, 4337–4340 (2001)

    Article  Google Scholar 

  9. Falciola, L. et al. High mobility group 1 (HMG1) protein is not stably associated with the chromosomes of somatic cells. J. Cell Biol. 137, 19–26 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zappavigna, V., Falciola, L., Helmer Citterich, M., Mavilio, F. & Bianchi, M. E. HMG1 cooperates with HOX proteins in DNA binding and transcriptional activation. EMBO J. 15, 4981–4991 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Phair, R. D. & Misteli, T. High mobility of proteins in the mammalian cell nucleus. Nature 404, 604–609 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Misteli, T., Gunjan, A., Hock, R., Bustin, M. & Brown, D. T. Dynamic binding of histone H1 to chromatin in living cells. Nature 408, 877–881 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Calogero, S. et al. The lack of chromosomal protein HMG1 does not disrupt cell growth, but causes lethal hypoglycaemia in newborn mice. Nature Genet. 22, 276–280 (1999)

    Article  CAS  PubMed  Google Scholar 

  14. Ura, K., Nightingale, K. & Wolffe, A. P. Differential association of HMG1 and linker histones B4 and H1 with dinucleosomal DNA: structural transitions and transcriptional repression. EMBO J. 15, 4959–4969 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nightingale, K., Dimitrov, S., Reeves, R. & Wolffe, A. P. Evidence for a shared structural role for HMG1 and linker histones B4 and H1 in organizing chromatin. EMBO J. 15, 548–561 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Enari, M. et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43–50 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Fadok, V. A., Bratton, D. L., Guthrie, L. & Henson, P. M. Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J. Immunol. 166, 6847–6854 (2001)

    Article  CAS  PubMed  Google Scholar 

  18. Thomas, S. H. L. Paracetamol (acetaminophen) poisoning. Pharmacol. Ther. 60, 91–120 (1993)

    Article  CAS  PubMed  Google Scholar 

  19. Lawson, J. A., Farhood, A., Hopper, R. D., Bajt, M. L. & Jaeschke, H. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol. Sci. 54, 509–516 (2000)

    Article  CAS  PubMed  Google Scholar 

  20. Ren, Y. & Savill, J. Apoptosis: the importance of being eaten. Cell Death Differ. 5, 563–568 (1998)

    Article  CAS  PubMed  Google Scholar 

  21. Scott, R. S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 211, 201–211 (2001)

    Google Scholar 

  22. Herrmann, M. et al. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 41, 1241–1250 (1998)

    Article  CAS  PubMed  Google Scholar 

  23. Bustin, M. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem. Sci. 26, 152–153 (2001)

    Article  CAS  PubMed  Google Scholar 

  24. Kato, A., Yoshidome, H., Edwards, M. J. & Lentsch, A. B. Regulation of liver inflammatory injury by signal transducer and activator of transcription-6. Am. J. Pathol. 157, 297–302 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank I. Benzoni and L. Ronfani for help with mouse experiments; T. Bonaldi, A. Gunjan, N. Bhattacharyya, R. Hock, M. Bustin, S. Nagata, F. Curnis, A. Corti and B. M. Turner for reagents; V. Caiolfa for help with preparing Cy5–HMGB1 and statistical analysis; S. Müller for instruction in preparing mouse bone marrow; and D. Donato for personal and technical support. A. Vecchi and A. Mantovani contributed unpublished results; and P. Dellabona, A. Manfredi, R. Pardi and several members of our group provided invaluable suggestions. This work was supported by the Italian Association for Cancer Research and by the Ministry for Education, University and Research.

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Authors and Affiliations

  1. DIBIT, Istituto Scientifico San Raffaele, 20132, Milano, Italy

    Paola Scaffidi

  2. National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA

    Tom Misteli

  3. Università Vita Salute San Raffaele, 20132, Milano, Italy

    Marco E. Bianchi

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  1. Paola Scaffidi
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Correspondence to Marco E. Bianchi.

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A patient application has been filed on HMGB1 as a signalling molecule.

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Scaffidi, P., Misteli, T. & Bianchi, M. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002). https://doi.org/10.1038/nature00858

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