Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway

Sun, Shilong; Duan, Zhiwen; Wang, Xinyu; Chu, Chengnan; Yang, Chao; Chen, Fang; Wang, Daojuan; Wang, Chenyang; Li, Qiurong; Ding, Weiwei

doi:10.1038/s41419-021-03896-1

Cited by 70 publications

(73 citation statements)

References 48 publications

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“…Abundant neutrophils were activated to release NETs in the gut in lipopolysaccharide- (LPS-) induced sepsis [ 45 ]. Elevated serum NETs are associated with intestinal injury in abdominal sepsis patients [ 44 ]. Sun et al [ 44 ] suggested that NETs activated endoplasmic reticulum (ER) stress in the lethal septic shock model.…”

Section: Nets and Intestinal Injuries During Sepsismentioning

confidence: 99%

“…Elevated serum NETs are associated with intestinal injury in abdominal sepsis patients [ 44 ]. Sun et al [ 44 ] suggested that NETs activated endoplasmic reticulum (ER) stress in the lethal septic shock model. TLR9 antagonist administration alleviated NET-induced damage in the intestinal epithelial cell monolayer through ER stress inhibition [ 44 ].…”

Section: Nets and Intestinal Injuries During Sepsismentioning

confidence: 99%

“…Sun et al [ 44 ] suggested that NETs activated endoplasmic reticulum (ER) stress in the lethal septic shock model. TLR9 antagonist administration alleviated NET-induced damage in the intestinal epithelial cell monolayer through ER stress inhibition [ 44 ]. Collectively, these findings demonstrated that the release of NETs may lead to intestinal damage during sepsis.…”

Section: Nets and Intestinal Injuries During Sepsismentioning

confidence: 99%

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Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology

Chen

Shao

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Many gut disease etiologies are attributed to the presence of robust inflammatory cell recruitment. The recruitment of neutrophils plays a vital role in inflammatory infiltration. Neutrophils have various antimicrobial effector mechanisms, including phagocytosis, oxidative burst, and degranulation. It is suggested that neutrophils could release neutrophil extracellular traps (NETs) to kill pathogens. However, recent evidence indicates that neutrophil infiltration within the gut is associated with disrupted local immunological microenvironment and impaired epithelial barrier. Growing evidence implies that NETs are involved in the progression of many diseases, including cancer, diabetes, thrombosis, and autoimmune disease. Increased NET formation was found in acute or chronic conditions, including infection, sterile inflammation, cancer, and ischemia/reperfusion injury (IRI). Here, we present a comprehensive review of recent advances in the understanding of NETs, focusing on their effects in gut disease. We also discuss NETs as a potential therapeutic target in gut disease.

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Section: Nets and Intestinal Injuries During Sepsismentioning

confidence: 99%

Section: Nets and Intestinal Injuries During Sepsismentioning

confidence: 99%

Section: Nets and Intestinal Injuries During Sepsismentioning

confidence: 99%

See 1 more Smart Citation

Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology

Chen

Shao

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Additionally, in the bleomycin pulmonary fibrosis model, IRE1-a inhibition reduces alveolar epithelial apoptosis and prevented fibrosis (24,25). Recently, crosstalk between NETs and ER stress has been observed in a model of sepsisinduced intestinal injury, with inhibition of NETosis and ER stress reducing intestinal epithelial cell monolayer barrier disruption, suggesting that neutrophils and NETosis contribute to ER stress in intestinal epithelial cells (26).…”

Section: Introductionmentioning

confidence: 99%

Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model

et al. 2022

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Diffuse alveolar hemorrhage (DAH), although rare, is a life-threatening complication of systemic lupus erythematosus (SLE). Little is known about the pathophysiology of DAH in humans, although increasingly neutrophils, NETosis and inflammatory monocytes have been shown to play an important role in the pristane-induced model of SLE which develops lung hemorrhage and recapitulates many of the pathologic features of human DAH. Using this experimental model, we asked whether endoplasmic reticulum (ER) stress played a role in driving the pathology of pulmonary hemorrhage and what role infiltrating neutrophils had in this process. Analysis of lung tissue from pristane-treated mice showed genes associated with ER stress and NETosis were increased in a time-dependent manner and reflected the timing of CD11b+Ly6G+ neutrophil accumulation in the lung. Using precision cut lung slices from untreated mice we observed that neutrophils isolated from the peritoneal cavity of pristane-treated mice could directly induce the expression of genes associated with ER stress, namely Chop and Bip. Mice which had myeloid-specific deletion of PAD4 were generated and treated with pristane to assess the involvement of PAD4 and PAD4-dependent NET formation in pristane-induced lung inflammation. Specific deletion of PAD4 in myeloid cells resulted in decreased expression of ER stress genes in the pristane model, with accompanying reduction in IFN-driven genes and pathology. Lastly, coculture experiments of human neutrophils and human lung epithelial cell line (BEAS-2b) showed neutrophils from SLE patients induced significantly more ER stress and interferon-stimulated genes in epithelial cells compared to healthy control neutrophils. These results support a pathogenic role of neutrophils and NETs in lung injury during pristane-induced DAH through the induction of ER stress response and suggest that overactivation of neutrophils in SLE and NETosis may underlie development of DAH.

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“…Neutrophil extracellular traps (NETs) are a new antimicrobial function of neutrophils; NETs are web-like structures accompanied by many proteins, histones, and DNA [ 6 ]. The formation of NETs is a double-edged sword in sepsis; NETs trap pathogens in the early stage, while cause NETs-associated injuries, such as coagulation, thrombotic disorders, and organ injury, in the later stage [ 7 – 9 ]. The balance between NETs formation and clearance plays a crucial role in sepsis.…”

Section: Introductionmentioning

confidence: 99%

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

et al. 2021

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Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.

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Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway

Cited by 70 publications

References 48 publications

Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology

Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology

Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

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