Dysregulation of neutrophil death in sepsis

Abstract

Sepsis is a prevalent disease that has alarmingly high mortality rates and, for several survivors, long-term morbidity. The modern definition of sepsis is an aberrant host response to infection followed by a life-threatening organ dysfunction. Sepsis has a complicated pathophysiology and involves multiple immune and non-immune mediators. It is now believed that in the initial stages of sepsis, excessive immune system activation and cascading inflammation are usually accompanied by immunosuppression. During the pathophysiology of severe sepsis, neutrophils are crucial. Recent researches have demonstrated a clear link between the process of neutrophil cell death and the emergence of organ dysfunction in sepsis. During sepsis, spontaneous apoptosis of neutrophils is inhibited and neutrophils may undergo some other types of cell death. In this review, we describe various types of neutrophil cell death, including necrosis, apoptosis, necroptosis, pyroptosis, NETosis, and autophagy, to reveal their known effects in the development and progression of sepsis. However, the exact role and mechanisms of neutrophil cell death in sepsis have not been fully elucidated, and this remains a major challenge for future neutrophil research. We hope that this review will provide hints for researches regarding neutrophil cell death in sepsis and provide insights for clinical practitioners.

Elevation of neutrophil-derived factors in patients after multiple trauma

“…Previously, we were able to demonstrate systemic neutrophil activation after burn injury 22 . This is in accord with other studies reporting a role for neutrophils and NETs in burn injury 27 ,, ,28 ,critically ill patients 21 , sepsis 29 , and lung injury 30 . Whereas NET formation represents a protective process that captures and sequesters microbes, thereby preventing the spread of infection, a dysregulation of NET formation with increased concentration of extracellular DNA may contribute to the perpetuation of in ammation and severe tissue injury 25,[31][32][33] .…”

“…Nineteen patients (18%) died during hospital stay. Injured patients presented with a median ISS of 34 [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] 2), but these differences were not signi cant.…”

Elevation of neutrophil‐derived factors in patients after multiple trauma

“…Previously, we were able to demonstrate systemic neutrophil activation after burn injury 12 . This is in accord with other studies reporting a role for neutrophils and NETs in burn injury, 17 critically ill patients, 11 sepsis 18 and lung injury 19 . Whereas NET formation represents a protective process that captures and sequesters microbes, thereby preventing the spread of infection, a dysregulation of NET formation with increased concentration of extracellular DNA may contribute to the perpetuation of inflammation and severe tissue injury 15,20 .…”

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

“…Bacterial products and over-release of pro-inflammatory cytokines such as TNF-α, IL-1b, IL-6, and IL-17 increase G-CSF expression and indirectly mobilize neutrophils by altering the balance between CXCR4 and CXCR2 ligands in bone marrow, affecting their release, activation, and migration ( 120 , 121 ). During sepsis, the spontaneous apoptosis of neutrophils is delayed, but other types of death such as necrosis, necroptosis, pyroptosis, NETosis, and autophagy may happen ( 10 , 116 , 122 ). It is well established that the proportion of neutrophil NETosis ( 123 ) and autophagy ( 124 ) increases in sepsis with reduced apoptosis ( 125 ), but the other three types of neutrophil death remain poorly understood ( Figure 1 ).…”

“…It is well-accepted that neutrophil dysfunction occurs in sepsis and has been considered the main cause of organ failure (27,(115)(116)(117). Neutrophil degranulation and endothelial dysfunction are shown to be the core events of the pathophysiology of sepsis (77, 118).…”