Role of Complement and Histones in Sepsis

Abstract

The wide use of the mouse model of polymicrobial sepsis has provided important evidence for events occurring in infectious sepsis involving septic mice and septic humans. Nearly 100 clinical trials in humans with sepsis have been completed, yet there is no FDA-approved drug. Our studies of polymicrobial sepsis have highlighted the role of complement activation products (especially C5a anaphylatoxin and its receptors C5aR1 and C5aR2) in adverse effects of sepsis. During sepsis, the appearance of these complement products is followed by appearance of extracellular histones in plasma, which have powerful proinflammatory and prothrombotic activities that cause cell injury and multiorgan dysfunction in septic mice. Similar responses occur in septic humans. Histone appearance in plasma is related to complement activation and appearance of C5a and its interaction with its receptors. Development of the cardiomyopathy of sepsis also depends on C5a, C5a receptors and histones. Neutralization of C5a with antibody or absence of C5aR1 blocks appearance of extracellular histones and cell and organ failure in sepsis. Survival rates in septic mice are greatly improved after blockade of C5a with antibody. We also review the various strategies in sepsis that greatly reduce the development of life-threatening events of sepsis.

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

“…Likewise, NETosis/ETosis, a regulated form of necrosis that is restricted to immune cells like neutrophils (NETosis) and other granulocytes or macrophages (ETosis), also contributes to the formation of CHs (20)(21)(22)(23)(24). In sepsis, the decondensed chromosome networks, termed as neutrophil extracellular traps (NETs), are mainly formed by neutrophil protrusions after stimulations of interleukin (IL)-8, lipopolysaccharide (LPS), TNF-a, complement, high hemodynamic forces and cold-inducible RNA-binding protein (11,(25)(26)(27)(28). Growing evidence have suggested that activation of TLR2/4 as well as complement play a significant role in initiating NETosis and mediating dysregulated innate immune response, forming a vicious cycle to cause subsequent tissue injury and organ dysfunction (29)(30)(31).…”

“…Sepsis is associated with the activation of all three complement pathways (classical, alternative and lectin), resulting in the appearance of proinflammatory anaphylatoxins C3a and C5a (28). Bosmann et al and Kalbitz et al collectively showed that the interaction between C5a and its receptor (C5aR1 and C5aR2) significantly contributed to the formation of extracellular histones that further mediated acute lung injury and cardiomyopathy in sepsis (29,44).…”

Erythrocytes as Biomarkers of Virus and Bacteria in View of Metal Ion Homeostasis

“…The immunosuppressed stage can last for many months or even years and comes with increased risk for death due to secondary infections. Many aspects of sepsis have been highlighted recently like the presence of exosomes [77], complement and histones [78], metabolic changes [79] and ROS and inflammasomes [80]. Gene expression analysis of sepsis patients revealed CXCL8, tumor protein P53 and TNF as particularly important based on a subsequent pathway analysis [81,82].…”

Elevated Serum C1q Levels in Children With Sepsis

“…The neutralization of C5a with antibodies or the absence of C5aR1 prevents the appearance of extracellular histones, cell death and organ failure in sepsis. Blocking C5a with antibodies can significantly improve the survival rate of septic mice (17); In addition to C5a, other complement components such as C3a, C4, FBP have many relevant studies in sepsis (14,18,19). Some scholars have found that when sepsis occurs, the complement system and neutrophils are activated by pathogens and endogenous danger signals at the same time.…”