Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

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 targets. Outside the cell, it binds with high affinity to RAGE (the receptor for advanced glycation end products) and is a potent mediator of inflammation. HMGB1 is secreted by activated monocytes and macrophages, and is passively released by necrotic or damaged cells. 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.

Cellular and molecular mechanisms in liver fibrogenesis

“…In particular, resident cells of innate immunity, through the binding to their pattern recognition receptors (PRRs), can either detect pathogen-associated molecular patterns (PAMPs) as well as damageassociated molecular patterns (DAMPs) from injured cells, the latter event leading to the so-called sterile inflammation [101]. Several DAMPs can be released or generated into the extracellular environment by dying cells or in relation to abnormal metabolism, and then trigger sterile inflammation, including proteins like: i) high-mobility group box 1 (HMGB1) [102], ii) heat shock proteins (HSPs) [103], iii) proteins of extracellular matrix generated following tissue injury (i.e., hyaluronan, heparin sulfate and biglycan) as modified/cleaved by enzymes released from dying cells or by other proteases [104,105]. Non-protein DAMPs such as ATP and uric acid (that) can be released or generated during cell injury and death [106]; mitochondria are a rich source of DAMPs like, in addition to ATP, mitochondrial DNA, formyl peptides and cytochrome C [107] which are effective stimulators of inflammation.…”

Apoptosis and necrosis mediate skeletal muscle fiber loss in age‐induced mitochondrial enzymatic abnormalities

“…Necrosis therefore frequently occurs during pathological conditions including stroke, ischemia, and neurodegenerative disorders (Syntichaki et al ., 2002; Malhi et al ., 2006; Henriquez et al ., 2008). Inflammation is associated with necrosis and not with apoptotic cell death (Scaffidi et al ., 2002). The complement system, a major component of innate immunity, responds to inflammation (Carroll, 2004).…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…High mobility group box 1 (HMGB1), another ligand for RAGE, is a nuclear DNA‐binding protein that can be actively secreted or passively released upon necrotic cell death (but not upon apoptosis) and exert proinflammatory effects by triggering myeloid cells to secrete substantial amounts of TNF‐ α , IL‐1 β , IL‐6, IL‐8, macrophage inflammatory protein (MIP)‐1 α , MIP‐1 β 303, 304, 305. HMGB1 is expressed and released by human skeletal muscle cells upon muscle injury and via binding to RAGE expressed on the surface of myoblasts faciliates myogenesis and muscle regeneration 306, 307…”