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Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

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.

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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 A. Vecchi and A. Mantovani contributed unpublished results; and P. Dellabona, A. Manfredi, R. Pardi and several members of our group provided invaluable suggestions.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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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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