Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

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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.