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.

Keywords: NETs; apoptosis; autophagy; cell death; necroptosis; neutrophil; pyroptosis; sepsis.

Figure 1

Association of different forms of programmed neutrophil cell death. The forms and specific mechanisms about neutrophil cell death in sepsis are not clear. Neutrophil apoptosis is delayed in sepsis, and necroptosis may occur when caspase-8 activity is inhibited. Neutrophils may release NETs through NETosis, and CitH3 in NETs may cause cell death as DAMPs. GSDMD, a key protein in pyroptosis, is involved in the release of NETs, and NE in NETs has the ability to cleave GSDMD to cause pyroptosis. Autophagy, as an intracellular degradation system, can recover harmful substances in cells and prevent the spread of inflammation, but it may assist in the formation of NETs despite of the ongoing controversy (, –36). The process of cell death usually begins at the receptor itself. However, the signaling cascade determines the fate of neutrophils to some extent. In addition, we summarized the therapeutic potential strategies of neutrophil death for sepsis, including induction of neutrophil apoptosis, GSDMD inhibition, anti-NETosis, and anti-DAMPs (Red Boxs).

Figure 2

Neutrophil apoptosis is inhibited in sepsis. Apoptosis is essential for regulating the lifespan of neutrophils. In sepsis, the execution of the neutrophil death program is delayed by various stimuli. Inhibition of neutrophil apoptosis or reduction of macrophage uptake of apoptotic neutrophils can exacerbate injury to tissues or organs. 50% of resting neutrophils exhibited apoptotic morphological changes after 24 hours, while the corresponding percentage for septic neutrophils was only 5 - 10%. A variety of anti-apoptotic signals produced during sepsis include preservation of Mcl-1 and Annexin A1, release of PBEF, IL-10, inhibition of MNDA translocation from nucleus to cytoplasm, inhibition of Caspase-3, -8 and -9 activation, and increased PD-L1 expression.

Figure 3

The difference between apoptosis and necroptosis. Caspase-8 largely determines whether cells undergo an apoptotic or necrotic program. After activation of caspase-8, the cells may undergo apoptosis; When it is inhibited, the cells may become necroptotic.

Figure 4

The key process of neutrophil pyroptosis in sepsis. In the classical pathway, pathogens, bacteria and other signals can recognize the intracellular NLR family and activate casepase-1 by forming inflammasome. Capsase-1 can cleave pro-IL-1β to IL-1β inducing inflammation. Whereas in the non-classical pathway, the participation of inflammasome is not necessary for the activation of caspase-4/5/11. Capsase-4/5/11 can cleave GSDMD to N-GSDMD and promote NET release. GSDMD can also be cleaved by NE to promote NETs release. Some possible targets for reducing NETs release during sepsis are pointed out.

Figure 5

Neutrophil NETosis in sepsis. Suicidal NETosis and vital NETosis are two types of NETosis that differ mainly in whether or not the neutrophils cleave. The primary function of vital NETosis is to offer extracellular antimicrobial effects, ensuring that neutrophils remain mobile and phagocytic, but too much NET release also cause injury. Suicidal NETosis primarily causes some damage to the body, but also provides microbicidal activity. NETs and their components, such as histones and DNA, are cytotoxic and have the ability to damage endothelial cells. Tissue factors can be created and released during the creation of NETs, triggering the coagulation cascade while also boosting platelet activation, resulting in platelet aggregation and ultimately inducing thrombosis formation. NETs may induce macrophage pyroptosis, which will aggravate the inflammatory responses during sepsis. In addition, NETs may induce M1-type polarization of macrophages of lung tissue, which increases lung inflammation and lung injury.

Figure 6

Role of autophagy in neutrophils. Autophagy is essential for regulating neutrophil function, such as metabolism, differentiation, degranulation, phagocytosis, cytokine production, and NET formation.