Histones are intra-nuclear cationic proteins that are present in all eukaryotic cells and are highly conserved acrosss pecies. Within the
nucleus, they provide structural stability to chromatin and regulate gene expression. Histone may be released into the extracellular space in three forms: freely, as a DNA-bound nucleosome or as part of neutrophil
extracellular traps, and all three can be deteted in serum after significant cellular death such as sepsis, trauma, ischaemia/reperfusion (I/R) injury and autoimmune disease. Once in the extracellular space, histones actas Damage-Associated Molecular Pattern (DAMP) proteins,
activating theimmune system and causing further cytotoxicity. They interact with Toll-Like Receptors (TLRs), complement and the phospholi
pids of cell membranes inducing endothelial and epithelial cytotoxicity, TLR2/TLR4/TLR9 activation and pro-inflammatory cytokine/chemokine release via MyD88, NFκB and NLRP3 inflammasome dependent pathways. Drugs that block the release of histone, neutralise circulating histone or block histone signal transduction provide significant protection from mortality in animal models of acute organ
injury but warrant further research to in form future clinical applications.