Dysregulation of neutrophil in sepsis: recent insights and advances

Abstract

Sepsis remains the leading cause of death in intensive care units. Despite newer antimicrobial and supportive therapies, specific treatments are still lacking. Neutrophils are pivotal components of the effector phase of the host immune defense against pathogens and play a crucial role in the control of infections under normal circumstances. In addition to its anti-infective effects, the dysregulation and overactivation of neutrophils may lead to severe inflammation or tissue damage and are potential mechanisms for poor prognosis in sepsis. This review focuses on recent advancements in the understanding of the functional status of neutrophils across various pathological stages of sepsis to explore the mechanisms by which neutrophils participate in sepsis progression and provide insights for the treatment of sepsis by targeting neutrophils.

Keywords: Neutrophil; Neutrophil extracellular traps; Organ injury; Oxidative stress; Sepsis.

Fig. 1

Changes in neutrophil behavior in sepsis. (A) During non-severe sepsis, neutrophils expressing CXCR2 are recruited from the blood to the infection site in response to CXCL2. Neutrophils migrate to the location of infection and kill pathogens by releasing antibacterial substances, such as ROS, NO, and NETs. Other immune cells, such as lymphocytes, can also migrate to the infection site to prevent the spread of pathogens. (B) However, during severe sepsis, neutrophils exhibit an increased lifespan and impaired function due to the downregulation of CXCR2 and upregulation of CCR2. Impaired migration results in pathogens’ spread. However, many neutrophils are confined to vessels and release NETs, resulting in vascular inflammation, endothelial damage, and thrombosis. NET formation can be classified into three types. The first type is suicidal NETosis, in which NETs are released via cell lysis. The second type allows NET release and the coexistence of conventional live neutrophil functions such as phagocytosis. The third type of NETosis is mtDNA NETosis. Viable neutrophils release mtDNA to form NETs, and this process does not depend on cell death but on ROS. (C) LPS and C5a in peripheral circulation can induce neutrophil resistance to apoptosis via three signalling pathways. Moreover, neutrophils induce lymphocyte apoptosis via PD-L1 up‐regulation. Additionally, CCR2, which is absent in neutrophils under normal conditions, is upregulated in neutrophils via TLR activation. CCR2 drives the inappropriate infiltration of neutrophils into remote organs that produce CCL2 and further elicits tissue damage in remote organs such as the lungs, liver, and kidneys

Fig. 2

Neutrophil markers implicated in sepsis. Abbreviations: CD, cluster of differentiation; CXCR, C-X-C chemokine receptor; miRNA, microRNA; OLMF, olfactomedin; RNA, ribonucleic acid; TCR, T-cell receptor

Fig. 3

Neutrophil migration and signal pathways underlying the impaired neutrophil migration into infection sites. 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 upregulation of GRK2, resulting in desensitization of CXCR2 on the surface of neutrophils. Administration of IL-33 reversed the effects of GRK2 on CXCR2 expression, driving neutrophils to migrate to the site of infection. Furthermore, TLR activation can upregulate CCR2 on the surface of neutrophils, favoring the recruitment of neutrophils to distant organs

Fig. 4

Functional changes in neutrophils during sepsis. Neutrophils produced in the bone marrow via granulopoiesis are released into circulation. These cells exhibited changes in markers, including CXCR4 and CD62L, depending on the age and activation status. Under homeostatic conditions, different infections and microenvironments result in diverse forms of cell death. These include apoptosis and various lytic death forms, such as necroptosis, pyroptosis, and NETosis, which are associated with the release of toxic cellular proteases, cell-free DNA, and chromatin into the microenvironment. These pathways are distinct molecular pathways regulated by immunosuppressive or inflammatory outcomes. Defects in the clearance process and the accumulation of cell remnants are responsible for the development of inflammatory diseases