Role of post-translational modifications in modulating histone reactivity in the extracellular environment

Histones are critical for the packaging of nuclear DNA and chromatin assembly, which is facilitated by the high abundance of lysine and arginine residues within these proteins. These residues are the site of post-translational modifications, which regulate cellular processes involving DNA, such as transcription, replication, and repair. Histones are also present in the extracellular environment, following their passive release by dying cells or active release by immune cells as extracellular traps. In the extracellular environment, histones are potent antimicrobial agents and play a role in limiting the spread of infection. However, there is strong evidence that extracellular histones are also involved in propagating disease, owing to their damaging reactions with host cells. Histones are cytotoxic and pro-inflammatory and drive coagulation, which has been associated with organ failure and death in both acute and chronic inflammatory diseases. The present review describes the reactivity of histones in the extracellular environment, with a particular focus on how these reactions are influenced by post-translational modifications relevant to physiological and pathological conditions.