A Comparative Review of Neutrophil Extracellular Traps in Sepsis

Abstract

Sepsis is the leading cause of critical illness and mortality in human beings and animals. Neutrophils are the primary effector cells of innate immunity during sepsis. Besides degranulation and phagocytosis, neutrophils also release neutrophil extracellular traps (NETs), composed of cell-free DNA, histones, and antimicrobial proteins. Although NETs have protective roles in the initial stages of sepsis, excessive NET formation has been found to induce thrombosis and multiple organ failure in murine sepsis models. Since the discovery of NETs nearly a decade ago, many investigators have identified NETs in various species. However, many questions remain regarding the exact mechanisms and fate of neutrophils following NET formation. In humans and mice, platelet-neutrophil interactions via direct binding or soluble mediators seem to play an important role in mediating NET formation during sepsis. Preliminary data suggest that these interactions may be species dependent. Regardless of these differences, there is increasing evidence in human and veterinary medicine suggesting that NETs play a crucial role in the pathogenesis of intravascular thrombosis and multiple organ failure in sepsis. Because the outcome of sepsis is highly dependent on early recognition and intervention, detection of NETs or NET components can aid in the diagnosis of sepsis in humans and veterinary species. In addition, the use of novel therapies such as deoxyribonuclease and non-anticoagulant heparin to target NET components shows promising results in murine septic models. Much work is needed in translating these NET-targeting therapies to clinical practice.

Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes

“…At the sites of infection, neutrophils can combat pathogenic microorganisms and clear infections by different ways including phagocytosis, degranulation of microbicidal molecules, production and secretion of reactive oxygen species (ROS), and release of neutrophil extracellular traps (NETs) [20]. For efficient bacterial phagocytosis, the microorganism needs to be covered with opsonins, such as immunoglobulins (Igs) and components of the complement system, which are recognized by neutrophil specific surface receptors.…”

“…Neutrophils may also perform the antimicrobial activity directly attacking and restraining microorganisms by releasing NETs (NETosis) [25,26]. NETs are extracellular fibrous structures composed by a network of extracellular chromatin fibers, histones, antimicrobial peptides, and enzymes, including MPO, α-defensins, cathepsin G, elastase, and lactoferrin, to capture and kill microorganisms [12,20,26]. NETosis occurs after neutrophil exposure to bacteria or stimulation with mediators such as interleukin CXCL8/IL-8.…”

“…NETosis occurs after neutrophil exposure to bacteria or stimulation with mediators such as interleukin CXCL8/IL-8. This neutrophil stimulation will result in activation of intracellular pro-inflammatory kinases, such as Akt, p38 MAPK, or MEK/ERK, a release of neutrophil elastase, oxidative burst, and actin polymerization [20,26,27]. This mechanism will result in microorganism destruction and neutrophil death [25].…”

“…This mechanism will result in microorganism destruction and neutrophil death [25]. NETs also limit the microorganism growth and dissemination; however, excessive formation of NETs in association with the uncontrolled inflammatory response that occurs in sepsis can result in multiple organ damage to the host [12,20].…”

Neutrophil extracellular trap stabilization leads to improved outcomes in murine models of sepsis

“…Cumulatively, our in vitro studies demonstrate that PF4 binding decreases NET toxicity by inhibiting NDP release and enhances bacterial entrapment by improving microbial capture and limiting susceptibility to DNase lysis (Figure 7). Based on these results, we speculated that PF4mediated NET compaction may be a conserved function that increases NET functionality while decreasing collateral host tissue damage in conditions such as sepsis in which overwhelming NET release occurs 45 . This theory in part stemmed from the observation that many species of bacteria release nucleases as a virulence factor to evade capture by NETs 46,47 .…”