Neutrophil dysregulation during sepsis: an overview and update

Abstract

Sepsis remains a leading cause of death worldwide, despite advances in critical care, and understanding of the pathophysiology and treatment strategies. No specific therapy or drugs are available for sepsis. Neutrophils play a critical role in controlling infection under normal conditions, and it is suggested that their migration and antimicrobial activity are impaired during sepsis which contribute to the dysregulation of immune responses. Recent studies further demonstrated that interruption or reversal of the impaired migration and antimicrobial function of neutrophils improves the outcome of sepsis in animal models. In this review, we provide an overview of the associated mediators and signal pathways involved which govern the survival, migration and antimicrobial function of neutrophils in sepsis, and discuss the potential of neutrophils as a target to specifically diagnose and/or predict the outcome of sepsis.

Keywords: neutrophil antimicrobial activity; neutrophil extracellular traps; neutrophil migration; sepsis; signal pathway.

Figure 1

Schematic depicting signal pathways of impaired neutrophil apoptosis during sepsis. During sepsis, C5a and LPS mainly mediate the increased lifespan of neutrophils through multisignal pathways. The activation of ERK1/2 and PI3K pathways by C5a and/or LPS can lead to the phosphorylation of Akt and subsequent phosphorylation of Bad, which inhibits cytochrome C release from mitochondria to prevent the formation of apoptosome. C5a can also enhance Bcl‐xL expression and reduce Bim expression. Moreover, LPS negatively influences MNDA relocation and cleavage and prevents proteasomal degradation of MCL‐1. All of these events favour the prolonged survival of neutrophils during sepsis.

Figure 2

Schematic depicting four phases of neutrophil migration in sepsis and signal pathways which accounts for the impaired migration of neutrophils into infection sites directed by CXCR2. During sepsis, neutrophils are systemically stimulated with impaired migration to the infection foci. Bacterial components can activate TLRs expressed on neutrophils and lead to the up‐regulation of GRK2, resulting in the desensitization of CXCR2 on the surface of neutrophils. Administration of IL‐33 can reverse the effects of GRK2 on CXCR2 expression, driving neutrophils migrating to the site of infection. In addition, activation of TLRs can also up‐regulate CCR2 on the surface of neutrophils, favouring the recruitment of neutrophils to distant organs.

Figure 3

NETs under normal condition and sepsis. The formation of NETs induced by pathogens is crucial for extracellular microbial trapping and killing. During sepsis, neutrophils accumulate and adhere to vascular endothelium in collaboration with platelets. They express tissue factor and expel tissue factor‐bearing NETs which could initiate the coagulation cascade. Moreover, the components of NETs also promote blood coagulation through numerous pathways.