The Protective Effect against Extracellular Histones Afforded by Long-Pentraxin PTX3 as a Regulator of NETs

Abstract

Pentraxin 3 (PTX3) is a soluble pattern recognition molecule that plays critical roles in innate immunity. Its fundamental functions include recognition of microbes, activation of complement cascades, and opsonization. The findings that PTX3 is one of the component proteins in neutrophil extracellular traps (NETs) and binds with other NET proteins imply the importance of PTX3 in the NET-mediated trapping and killing of bacteria. As NETs play certain critically important host-protective roles, aberrant NET production results in tissue damage. Extracellular histones, the main source of which is considered to be NETs, are mediators of septic death due to their cytotoxicity toward endothelial cells. PTX3 protects against extracellular histones-mediated cytotoxicity through coaggregation. In addition to the anti-bacterial roles performed in coordination with other NET proteins, PTX3 appears to mitigate the detrimental effect of over-activated NETs. A better understanding of the role of the PTX3 complexes in NETs would be expected to lead to new strategies for maintaining a healthy balance between the helpful bactericidal and undesirable detrimental activities of NETs.

Increased Circulating Levels of Neutrophil Extracellular Traps During Cardiopulmonary Bypass

“…It is hypothesized that PTX3 may act to protect against the adverse consequences of NETs by binding circulating histone, thereby preventing endothelial injury and acting as an antiinflammatory mediator in patients undergoing cardiac surgery. 44,45 We observed that the PTX3 level increased during the perioperative period and reached abnormal levels (> 2000 pg/mL) after CPB, but did not reach high levels commonly seen in sepsis (> 14,000 pg/mL). 46,47 Additionally, we found no correlations between PTX3 and NETs measurements during the perioperative period.…”

The long pentraxin PTX3: A prototypical sensor of tissue injury and a regulator of homeostasis

“…132,133 NETs have tissue-damaging and thrombogenic actions, at least partially mediated by histones. The ability of PTX3 to quench the potentially deleterious actions of histones [134][135][136] raises the interesting possibility that not all NETs are created equal, but that the rate of association with innate immune signals might modify their impact on the microenvironment. Further studies in vitro and in patients' tissues (see below) are necessary to validate this hypothesis.…”

Extracellular histones play a pathogenic role in primary graft dysfunction after human lung transplantation

“…Neutralization of extracellular histones has been reported to be protective in various inammatory conditions. 21,22 Here we investigated whether heparin, which is able to bind histones, 23 would diminish the observed effects of histones on the cells. Antihistone H4 antibody was applied as the control.…”