Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

Abstract

Histones are positively charged nuclear proteins that facilitate packaging of DNA into nucleosomes common to all eukaryotic cells. Upon cell injury or cell signalling processes, histones are released passively through cell necrosis or actively from immune cells as part of extracellular traps. Extracellular histones function as microbicidal proteins and are pro‐thrombotic, limiting spread of infection or isolating areas of injury to allow for immune cell infiltration, clearance of infection and initiation of tissue regeneration and repair. Histone toxicity, however, is not specific to microbes and contributes to tissue and end‐organ injury, which in cases of systemic inflammation may lead to organ failure and death. This review details the processes of histones release in acute inflammation, the mechanisms of histone‐related tissue toxicity and current and future strategies for therapy targeting histones in acute inflammatory diseases.

Extracellular histones are clinically associated with primary graft dysfunction in human liver transplantation

“…6,8 Recently, extracellular histones have been characterized as key mediators of I/R injuries in many organs including the liver, kidney, heart, and brain. [9][10][11] Extracellular histones increase remarkably aer I/ R injury, which are either released passively by stressed or injured cells, or are actively secreted by innate immune cells (e.g. neutrophils, monocytes/macrophages).…”

“…12,13 Extracellular histones not only correlate with disease severity and poor outcomes, which can reect ongoing cellular damage or the inammatory states, but also serve as a therapeutic target for I/ R injury. 11,14 Targeting extracellular histones attenuates the I/R injury of many organs. 14,15 The mechanisms of histone-mediated injury are yet to be fully understood.…”

Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome

“…Because extracellular histones are cytotoxic DAMP molecules, it is rational that the damaging effects can be ameliorated through the application of histone-targeted interventions [53]. Administration of speci c blocking antibodies or peptides targeted to these extracellular histones could inhibit in ammatory damage and improve outcomes in several types of animal models, such as sepsis, acute lung injury, liver injury, acute pancreatitis, and multiple organ injury [10,[54][55][56][57].…”

Histone H4 Aggravates Inflammatory Injury Mainly Through TLR4 in Chlorine Gas Induced Acute Respiratory Distress Syndrome

“…By contrast, nucleosomes, composed of histones and DNA, appear to be less toxic [22,23]. Extracellular histones cause direct cytotoxicity by binding phospholipids, disrupting cell membranes, and causing calcium influx [24][25][26]. More importantly, extracellular histones serve as DAMPs molecules to promote inflammation.…”