Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis

Zhang, Hao; Wang, Yanghanzhao; Qu, Mengdi; Li, Wenqian; Wu, Dan; Cata, Juan P.; Chen, Miao

doi:10.1002/ctm2.1170

Cited by 103 publications

(65 citation statements)

References 204 publications

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“…Sepsis is identified as life‐threatening organ dysfunction and leads to high mortality 19,20 . Our previous study found that STING is involved in sepsis‐related organ dysfunction and systemic inflammation 8 .…”

Section: Resultsmentioning

confidence: 99%

“…Sepsis is identified as life-threatening organ dysfunction and leads to high mortality. 19,20 Our previous study found that STING is involved in sepsis-related organ dysfunction and systemic inflammation. 8 In this study, we also found that RIPK1 and RIPK3, which are key proteins involved in necroptosis, were significantly upregulated in patients with sepsis and septic shock (Figures 8A and D).…”

Section: Inhibition Of Necroptotic Signalling Protects Against Sepsis...mentioning

confidence: 99%

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RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis

Zhang

Liu

et al. 2023

Clinical & Translational Med

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Backgrounds The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. Methods and results Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT‐29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL‐mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro‐necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA‐induced intestinal injury and sepsis. Conclusions These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING‐driven inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Inhibition Of Necroptotic Signalling Protects Against Sepsis...mentioning

confidence: 99%

RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis

Zhang

Liu

et al. 2023

Clinical & Translational Med

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“…However, NET components can also serve as DAMPs, which may induce a persistent inflammatory response and tissue damage 40 . According to our previous study, NETs aggravated systemic inflammation via the release of TNF‐1α, IL‐1β and IL‐6, 26 and such inflammatory cytokines could further induce NET formation, forming a vicious circle 41 . NETs can also interact with platelets, triggering extensive ‘immunothrombosis’ 42 .…”

Section: Discussionmentioning

confidence: 99%

METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

Zhang,

Wu,

Wang

et al. 2023

Clinical & Translational Med

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Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis‐induced acute lung injury (SI‐ALI). We demonstrate that NETs induce SI‐ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI‐ALI is accompanied by upregulation of ferroptosis depending on METTL3‐induced m6A modification of hypoxia‐inducible factor‐1α (HIF‐1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI‐ALI caused by NETs in a caecum ligation and puncture (CLP)‐induced SI‐ALI model using METTL3 condition knockout (CKO) mice and wild‐type mice. Our results indicate the crucial role of NETs in the progression of SI‐ALI via NET‐activated METTL3 m6A‐IGF2BP2‐dependent m6A modification of HIF‐1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.

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“…Endothelial cell adhesion molecules bind to leukocytes, thereby activating them and leading to their infiltration into the underlying tissues ( 54 ). Activated leukocytes not only block microvessels, but also cause an increase in the vascular permeability ( 55 ). Compared with those in control mice, the levels of the plasma pro-inflammatory factors, IL-6 and TNF-α, were found to be significantly increased following lipid emulsion infusion.…”

Section: Discussionmentioning

confidence: 99%

Free fatty acids induce coronary microvascular dysfunction via inhibition of the AMPK/KLF2/eNOS signaling pathway

Zhang¹,

Zhao²,

Ren³

et al. 2023

Int J Mol Med

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Increased levels of serum free fatty acids (FFAs) are closely associated with microvascular dysfunction. In our previous study, a coronary microvascular dysfunction (CMD) model was successfully established via lipid infusion to increase the levels of serum FFAs in mice. However, the underlying mechanisms remained poorly understood. Therefore, the aim of the present study was to explore the mechanism underlying FFA-induced CMD. A CMD mouse model was established via lipid combined with heparin infusion for 6 h to increase the concentration of serum FFAs. Following the establishment of the model, the coronary flow reserve (CFR), extent of leukocyte activation and cardiac microvascular structures were assessed in the mice. Cardiac microvascular endothelial cells (CMECs) were treated with different concentrations of palmitic acid and cell viability was evaluated. Changes in the expression levels of AMP-activated protein kinase (AMPK), Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS) were identified by immunohistochemical and western blot analyses. Experiments using AMPK activator, KLF2 overexpression plasmid, small interfering RNAs and nicorandil were subsequently designed to investigate the potential involvement of the AMPK/KLF2/eNOS signaling pathway. These experiments revealed that FFAs could induce CMD in mice, which was characterized by reduced CFR (1.89±0.37 vs. 2.74±0.30) and increased leukocyte adhesion (4,350±1,057.5 vs. 11.8±5.4 cells/mm 2 ) compared with the control mice. CD11b expression and intracellular reactive oxygen species (ROS) levels were increased in CMD model mice compared with control mice. Serum TNF-α and IL-6 levels were higher in the model group than in the control group. Transmission electron microscopy revealed that CMECs in heart tissues of model mice were severely swollen. In addition, palmitic acid decreased CMEC viability and increased ROS production in a dose-dependent manner. Notably, the AMPK/KLF2/eNOS signaling pathway was demonstrated to be suppressed by FFAs both in vivo and in vitro . Activation of this axis with AMPK activator, KLF2 overexpression plasmid or nicorandil restored the CFR in CMD model mice, inhibited oxidative stress and increased CMEC viability. Taken together, the results of the present study demonstrated that FFAs could induce CMD via inhibition of the AMPK/KLF2/eNOS signaling pathway, whereas activation of this pathway led to the alleviation of FFA-induced CMD, which may be a therapeutic option for CMD.

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Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis

Cited by 103 publications

References 204 publications

RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis

RIPK3–MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis

METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

Free fatty acids induce coronary microvascular dysfunction via inhibition of the AMPK/KLF2/eNOS signaling pathway

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