Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression

Zhao, Shuai; Chen, Fan; Yin, Qiliang; Wang, Dunwei; Han, Wei; Zhang, Yuan

doi:10.3389/fphys.2020.571810

Cited by 68 publications

(41 citation statements)

References 158 publications

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“…In patients with fatal sepsis, markedly increased production of ROS in neutrophils was observed (Santos et al, 2012). Uncontrolled release of ROS accumulating in vascular beds can contribute to the loss of endothelial barrier integrity and subsequent vascular leakage, leading to organ injury such as acute lung injury (Fox et al, 2013;Zhao et al, 2020). In line with these findings, patients with increased ROS production were more prone to develop ARDS than control patients (Kellner et al, 2017).…”

Section: Detrimental Effects Of Improper Activation Of Neutrophilsmentioning

confidence: 74%

Targeting Neutrophils in Sepsis: From Mechanism to Translation

et al. 2021

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Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Although our understanding in the pathophysiological features of sepsis has increased significantly during the past decades, there is still lack of specific treatment for sepsis. Neutrophils are important regulators against invading pathogens, and their role during sepsis has been studied extensively. It has been suggested that the migration, the antimicrobial activity, and the function of neutrophil extracellular traps (NETs) have all been impaired during sepsis, which results in an inappropriate response to primary infection and potentially increase the susceptibility to secondary infection. On the other hand, accumulating evidence has shown that the reversal or restoration of neutrophil function can promote bacterial clearance and improve sepsis outcome, supporting the idea that targeting neutrophils may be a promising strategy for sepsis treatment. In this review, we will give an overview of the role of neutrophils during sepsis and discuss the potential therapeutic strategy targeting neutrophils.

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Section: Detrimental Effects Of Improper Activation Of Neutrophilsmentioning

confidence: 74%

Targeting Neutrophils in Sepsis: From Mechanism to Translation

et al. 2021

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“…When sepsis occurs, hepatocytes undergo pathological hypoxia, leading to disorder of mitochondrial oxidative phosphorylation, mitochondrial dysfunction and the production of massive ROS [ 29 , 30 ]. And ROS is a key regulatory signal for the activation of NLRP3 inflammasome [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis

Zhang

Wang

et al. 2021

Aging

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Sepsis is a common critical illness in ICU and always a great difficulty in clinical treatment. GPR43 (G protein-coupled receptor 43) participates in regulating appetite and gastrointestinal peptide secretion to modulate fat decomposition and formation. However, the biological contribution of GPR43 on inflammation of sepsis has not been previously investigated. We investigated the mechanisms of GPR43 gene, which plays a possible role in distinguishing sepsis and contributes to the pathogenesis of sepsis-induced inflammatory reaction. Furthermore, we performed studies with mice induced to sepsis by Cecal Ligation and Puncture (CLP), Knockout GPR43 (GPR43-/-) mice, and Wild Type (WT) mice induced with CLP. In addition, lung tissues and cell samples were analyzed by histology, Quantitative Polymerase Chain Reaction (Q-PCR), Enzyme-linked Immunosorbent (ELISA) Assay, and western blot. GPR43 agonist could significantly reduce inflammation reactions and trigger lung injury in mice with sepsis. As for GPR43-/- mice, the risks of sepsis-induced inflammatory reactions and corresponding lung injury were promoted. On the one hand, the up-regulation of GPR43 gene reduced ROS mitochondrial damage to inhibit inflammatory reactions via the inactivation of NLRP3 Inflammasome by PPARγ/ Nox1/EBP50/ p47phox signal channel. On the other hand, the down-regulation of GPR43 promoted inflammatory reactions in vitro model through the acceleration of ROS-dependently mitochondrial damage by PPARγ/ Nox1/EBP50/ p47phox/ NLRP3 signal channel. These findings indicate that the inhibition of GPR43 as a possible important factor of sepsis may shed lights on the mechanism of sepsis-induced inflammation reaction.

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“…This suggests that inhibition of mitochondrial stress by small-molecule inhibitors could be an efficient strategy to suppress the activation of the NLRP3 inflammasome. Mitochondrial dysfunction in connection with NLRP3 inflammasome activation has been reported to play a role in inflammatory diseases such as diabetes, atherosclerosis, neurological disorders, cardiovascular disease, and kidney disease [ 19 , 20 ]. Therefore, the beneficial effects of loganin on mitochondrial dysfunction could be applied to other NLRP3-related diseases.…”

Section: Discussionmentioning

confidence: 99%

Loganin Alleviates Gout Inflammation by Suppressing NLRP3 Inflammasome Activation and Mitochondrial Damage

et al. 2021

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Gout is a type of inflammatory arthritis caused by the deposition of monosodium uric acid (MSU) crystals in tissues. The etiology of gout is directly linked to the NLRP3 inflammasome, since MSU crystals are NLRP3 inflammasome activators. Therefore, we decided to search for a small-molecule inhibitor of the NLRP3 inflammasome for the prevention of gout inflammation. We found that loganin suppressed MSU crystals-induced caspase-1 (p20) and interleukin (IL)-1β production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks formation in mouse primary macrophages, showing its ability to inhibit the NLRP3 inflammasome. In an air pouch inflammation model, oral administration of loganin to mice prevented MSU crystals-induced production of mature IL-1β and IL-18 in air pouch exudates, resulting in decreased neutrophil recruitment. Furthermore, oral administration of loganin suppressed MSU crystals-induced gout inflammation in a mouse foot gout model, which was accompanied by the inhibition of the NLRP3 inflammasome. Loganin blocked de novo synthesis of mitochondrial DNA in air pouches and foot tissues injected with MSU crystals. Consistently, loganin prevented MSU crystals-induced mitochondrial damage in macrophages, as it increased mitochondrial membrane potential and decreased the amount of mitochondrial reactive oxygen species. These data demonstrate that loganin suppresses NLRP3 inflammasome activation by inhibiting mitochondrial stress. These results suggest a novel pharmacological strategy to prevent gout inflammation by blocking NLRP3 inflammasome activation and mitochondrial dysfunction.

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Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression

Cited by 68 publications

References 158 publications

Targeting Neutrophils in Sepsis: From Mechanism to Translation

Targeting Neutrophils in Sepsis: From Mechanism to Translation

GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis

Loganin Alleviates Gout Inflammation by Suppressing NLRP3 Inflammasome Activation and Mitochondrial Damage

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