Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

Abstract

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with high morbidity and mortality. Circulating histones (CHs), a group of damage-associated molecular pattern molecules mainly derived from neutrophil extracellular traps, play a crucial role in sepsis by mediating inflammation response, organ injury and death through Toll-like receptors or inflammasome pathways. Herein, we first elucidate the molecular mechanisms of histone-induced inflammation amplification, endothelium injury and cascade coagulation activation, and discuss the close correlation between elevated level of CHs and disease severity as well as mortality in patients with sepsis. Furthermore, current state-of-the-art on anti-histone therapy with antibodies, histone-binding proteins (namely recombinant thrombomodulin and activated protein C), and heparin is summarized to propose promising approaches for sepsis treatment.

Keywords: circulating histones; coagulation; cytotoxicity; heparin; inflammation; sepsis; survival.

Figure 1

Proposed immunopathological roles of circulating histones in sepsis. In sepsis, inflammatory mediators including pathogen associated molecule patterns (PAMPs, namely bacteria and LPS etc.) and damage associated molecule patterns (DAMPs, namely IL-18, TNF-α and high mobility group box 1 etc.) activate innate immune cells (neutrophils and macrophages) and endothelial cells through pattern recognition receptors (toll-like receptors, C-type lectin receptors, and NOD-like receptors), initiating transcription of type I interferons and proinflammatory cytokines and triggering highly inflammatory programmed cell death such as NETosis/ETosis, necroptosis, necrosis and pyroptosis. Rupture of the plasma cell membrane of these cells contributes to the release of histones into extracellular spaces. Histones trigger innate immunity by activating Toll-like receptor (TLR) 2/4/9 or NLPR3 inflammasome pathways, leading to the release of pro-inflammatory cytokines (IL-1, IL-1β, IL-6, IL-18, TNF-α etc.) that not only cause neutrophils to release extracellular traps in return but also upregulate tissue factor (TF) expression by blood monocytes. Histones bind to endothelium cells and cause cell permeabilization, calcium influx and endothelium injury. Endothelium injury further induces barrier dysfunction, leakage of plasma-protein-rich fluid into the tissues, alteration of blood flow dynamics, recruitment and activation of circulating leucocytes and release of excessive cytokines, which are characterized by increased TF, prostacyclin (PGI2) and superoxide expression, decreased thromboxane A2 (TXA2) and nitric oxide release. Increased TF can trigger the activation of prothrombin through extrinsic coagulation pathway and finally cause disseminated intravenous coagulation (DIC). Besides, histones can directly activate thrombin formation by binding to prothrombin fragments 1 and 2 to form histone-prothrombin-FXa complex. Histones also induce platelet aggregation, activation and subsequent platelet-dependent thrombin formation through TLR2 and TLR4 pathways. Finally, dysregulated inflammation response, impaired endothelial barrier, immunothrombosis and DIC collectively cause multiple organ dysfunction (MODS) including circulatory failure, acute respiratory distress syndrome (ARDS), renal failure and liver failure, resulting in death in most severe form of sepsis.