Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

Chen, Zhaoyuan; Zhang, Hao; Qu, Mengdi; Nan, Ke; Cao, Hanzhong; Cata, Juan P.; Chen, Wankun; Chen, Miao

doi:10.3389/fcimb.2021.653228

Cited by 66 publications

(62 citation statements)

References 86 publications

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“…Protein scores were computed as the mean of the median-MAD column based on normalized protein abundance (compare Supplemental Table 1 ). Scores were determined after an extensive literature search: For granule scores, Adrover et al ( 38 ) was used as a reference, for procoagulant and complement groups, all detectable coagulation cascade factors and complement factors were included ( 71 – 75 ). For IL-8–related proteins, a literature search for detectable relevant pathway proteins was used for the score ( 76 – 88 ).…”

Section: Methodsmentioning

confidence: 99%

“…Table 1). Scores were determined after an extensive literature search: For granule scores, Adrover et al (38) was used as a reference, for procoagulant and complement groups, all detectable coagulation cascade factors and complement factors were included (73)(74)(75)(76)(77). For IL-8-related proteins, a literature search for relevant pathway proteins that were detectable were used for the score (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90).…”

Section: Data Analysis and Statisticsmentioning

confidence: 99%

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Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19

Kaiser¹,

Leunig²,

Pekayvaz³

et al. 2021

JCI Insight

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Neutrophils provide a critical line of defense in immune responses to various pathogens, but also inflict self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients suffering from COVID-19. Here, we utilize state-of-the art mass spectrometry-based proteomics, transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic interleukin-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophildriven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces SARS-CoV-2 spike protein-induced, hACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8-axis as promising therapeutic target in severe SARS-CoV-2 infection.

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Section: Methodsmentioning

confidence: 99%

Section: Data Analysis and Statisticsmentioning

confidence: 99%

Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19

Kaiser¹,

Leunig²,

Pekayvaz³

et al. 2021

JCI Insight

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“…Immune-thrombi formation occurs after contact of activated platelets with polymorphonuclear cells [79]. Many works on sepsis have also demonstrated this phenomenon [24,[80][81][82][83]. In addition, the participation of interleukin-1β (IL-1β), a pro-inflammatory cytokine, in the tissue factor (TF) release and NETs formation in atherothrombotic events has also been indicated [84].…”

Section: Neutrophilsmentioning

confidence: 97%

The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

Conceição-Silva

Reis

Luca

et al. 2021

Cells

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The first formal description of the microbicidal activity of extracellular traps (ETs) containing DNA occurred in neutrophils in 2004. Since then, ETs have been identified in different populations of cells involved in both innate and adaptive immune responses. Much of the knowledge has been obtained from in vitro or ex vivo studies; however, in vivo evaluations in experimental models and human biological materials have corroborated some of the results obtained. Two types of ETs have been described—suicidal and vital ETs, with or without the death of the producer cell. The studies showed that the same cell type may have more than one ETs formation mechanism and that different cells may have similar ETs formation mechanisms. ETs can act by controlling or promoting the mechanisms involved in the development and evolution of various infectious and non-infectious diseases, such as autoimmune, cardiovascular, thrombotic, and neoplastic diseases, among others. This review discusses the presence of ETs in neutrophils, macrophages, mast cells, eosinophils, basophils, plasmacytoid dendritic cells, and recent evidence of the presence of ETs in B lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes. Moreover, due to recently collected information, the effect of ETs on COVID-19 is also discussed.

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“…Neutrophils are the first line of defense against bacterial infection, and the formation of neutrophil extracellular traps (NETs) is an important protective mechanism [73]. However, NETs can also cause harm by exposing cytotoxic histones and promoting intravascular coagulation and tissue damage in sepsis [74][75][76]. Neutrophils activated by PAMPs, DAMPs, cytokines, and other dangerous molecules are thought to be important immune cells that cause tissue damage [77].…”

Section: Neutrophilsmentioning

confidence: 99%

Targeting Cytokines, Pathogen-Associated Molecular Patterns, and Damage-Associated Molecular Patterns in Sepsis via Blood Purification

Moriyama

Nishida

2021

IJMS

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Sepsis is characterized by a dysregulated immune response to infections that causes life-threatening organ dysfunction and even death. When infections occur, bacterial cell wall components (endotoxin or lipopolysaccharide), known as pathogen-associated molecular patterns, bind to pattern recognition receptors, such as toll-like receptors, to initiate an inflammatory response for pathogen elimination. However, strong activation of the immune system leads to cellular dysfunction and ultimately organ failure. Damage-associated molecular patterns (DAMPs), which are released by injured host cells, are well-recognized triggers that result in the elevation of inflammatory cytokine levels. A cytokine storm is thus amplified and sustained in this vicious cycle. Interestingly, during sepsis, neutrophils transition from powerful antimicrobial protectors into dangerous mediators of tissue injury and organ dysfunction. Thus, the concept of blood purification has evolved to include inflammatory cells and mediators. In this review, we summarize recent advances in knowledge regarding the role of lipopolysaccharides, cytokines, DAMPs, and neutrophils in the pathogenesis of sepsis. Additionally, we discuss the potential of blood purification, especially the adsorption technology, for removing immune cells and molecular mediators, thereby serving as a therapeutic strategy against sepsis. Finally, we describe the concept of our immune-modulating blood purification system.

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Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

Cited by 66 publications

References 86 publications

Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19

Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19

The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

Targeting Cytokines, Pathogen-Associated Molecular Patterns, and Damage-Associated Molecular Patterns in Sepsis via Blood Purification

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