OX40 expression in neutrophils promotes hepatic ischemia/reperfusion injury

Jin, Hua; Zhang, Chunpan; Sun, Chengyang; Zhao, Xinyan; Tian, Dan; Shi, Wei; Tian, Yue; Li, Kai; Sun, Guan; Xu, Huji; Zhang, Dong

doi:10.1172/jci.insight.129736

Cited by 19 publications

(16 citation statements)

References 42 publications

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“…# P < 0.05 vs. MCDHF-treated alone. inflammation 32,33,[46][47][48] . NETosis is a novel form of cell death without DNA fragmentation and allows neutrophils to fulfill their capacity beyond lifespan.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils undergo switch of apoptosis to NETosis during murine fatty liver injury via S1P receptor 2 signaling

et al. 2020

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Inappropriate neutrophil infiltration and subsequent neutrophil extracellular trap (NET) formation have been confirmed to be involved in chronic inflammatory conditions. Fatty liver disease is an increasingly severe health problem worldwide and currently considered the most common cause of chronic liver disease. Sphingosine 1-phosphate (S1P), a product of membrane sphingolipid metabolism, regulates vital physiological and pathological actions by inducing infiltration and activation of various cell types through S1P receptors (S1PRs). Here, we seek to determine the S1PR-mediated effects on neutrophil activation during chronic liver inflammation. In this study, NETs are detected in the early stage of methionine-choline-deficient and a high-fat (MCDHF) diet-induced liver injury. NET depletion by deoxyribonuclease I intraperitoneal injection significantly protects liver from MCDHF-induced liver injury in vivo. Meanwhile, we show that levels of myeloperoxidase-DNA complex (NET marker) in the serum present positive correlation with sphingosine kinase1 (S1P rate-limiting enzyme) messenger RNA expression or S1P levels in the injured liver of MCDHF-fed mice. In vitro, S1PR2 participates in the redirection of neutrophil apoptosis to NETosis via Gαi/o, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and reactive oxygen species signaling pathways. Moreover, S1PR2 knockdown in MCDHF-fed mice by S1PR2-siRNA intravenous injection significantly inhibits NET formation in damaged liver tissue and then alleviates hepatic inflammation and fibrosis. Conclusion: In the early stage of fatty liver disease, S1PR2-mediated neutrophil activation plays an important role in the evolvement of liver injury.

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Section: Discussionmentioning

confidence: 99%

Neutrophils undergo switch of apoptosis to NETosis during murine fatty liver injury via S1P receptor 2 signaling

et al. 2020

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“…We suspect that coordination of, and regulation by, canonical and non-canonical NF-kB pathways may also be related to local increased expression of TNFRSF4, MT2A, and PIM3 that we observed in our analysis [45]. Indeed, TNFRSF4, or OX40, encodes a ligand receptor of the TNF superfamily that is typically expressed by T-cells 24-72 h after activation [46][47][48][49][50][51][52][53]. This receptor has been shown to activate NF-kB via its interaction with adaptor proteins TRAF2 and TRAF5 (non-canonical).…”

Section: Discussionmentioning

confidence: 94%

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Tutino

Ishii

et al. 2021

Diagnostics

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The rupture of an intracranial aneurysm (IA) causes devastating hemorrhagic strokes. Yet, most IAs remain asymptomatic and undetected until they rupture. In the search for circulating biomarkers of unruptured IAs, we previously performed transcriptome profiling on whole blood and identified an IA-associated panel of 18 genes. In this study, we seek to determine if these genes are also differentially expressed within the IA lumen, which could provide a mechanistic link between the disease and the observed circulating gene expression patterns. To this end, we collected blood from the lumen of 37 IAs and their proximal parent vessels in 31 patients. The expression levels of 18 genes in the lumen and proximal vessel were then measured by quantitative polymerase chain reaction. This analysis revealed that the expression of 6/18 genes (CBWD6, MT2A, MZT2B, PIM3, SLC37A3, and TNFRSF4) was significantly higher in intraluminal blood, while the expression of 3/18 genes (ST6GALNAC1, TCN2, and UFSP1) was significantly lower. There was a significant, positive correlation between intraluminal and proximal expression of CXCL10, MT2A, and MZT2B, suggesting local increases of these genes is reflected in the periphery. Expression of ST6GALNAC1 and TIFAB was significantly positively correlated with IA size, while expression of CCDC85B was significantly positively correlated with IA enhancement on post-contrast MRI, a metric of IA instability and risk. In conclusion, intraluminal expression differences in half of the IA-associated genes observed in this study provide evidence for IA tissue-mediated transcriptional changes in whole blood. Additionally, some genes may be informative in assessing IA risk, as their intraluminal expression was correlated to IA size and aneurysmal wall enhancement.

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“…The bounding of OX40-OX40L play a critical role of regulating the activity of T cell and inflammatory cytokines production, associated closely with the proliferation, differentiation, or activation of CD4 + or CD8 + T cells [ 37 , 38 ]. Recent study found that OX40 expressed in innate immune cells such as neutrophils, contributing to the prolonged neutrophils survival, and promoted proinflammatory cytokines, ROS production, while Ox40 knockout markedly alleviated liver injury [ 39 ]. In the present study, the intervention with LNT downregulated significantly the levels of OX40, indicating the decreases of innate immune cells and adaptive immune helper T cells, contributing to the amelioration of inflammation in liver.…”

Section: Discussionmentioning

confidence: 99%

Lentinan alleviates arsenic-induced hepatotoxicity in mice via downregulation of OX40/IL-17A and activation of Nrf2 signaling

Yang

Song

Yuan-yuan

et al. 2022

BMC Pharmacol Toxicol

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Background Arsenic, existing ubiquitously in soil, drinking water, or food, is well known to be an environmental pollutants concerned by European Food Safety Authority. Lentinan, a beta-1,6;1,3-glucan extracts from Lentinus edodes, which has the properties of antioxidant and immunomodulation, present study explored the pharmacological effects of Lentinan on arsenic induced hepatotoxicity in mice. Methods Mice experiments were performed by sodium arsenite (SA) treatment or Lentinan intervention, then histopathology, ELISA, Flow Cytometry, or Western-Blotting were applied to evaluate hepatic injury, oxidative stress, CD4+ type 17 helper T (Th17) cells, CD4+CD25+Foxp3+ regulatory T cells (Tregs), T cells receptor OX40/CD134, IL-17A, NLRP3, Nrf2, and NQO1. Results SA treatment showed hepatic pathological injury and the elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in serum, and induced the increases of malondialdehyde (MDA), Th17 cells, OX40 or IL-17A in liver tissues, which were consistently ameliorated by Lentinan intervention. Further, immunoblotting experiments showed that Lentinan intervention downregulated the levels of OX40, IL-17A, and NLRP3 signals, while elevated the levels of anti-oxidative Nrf2, NQO1 signals compared to arsenic treatment group. For Tregs, Lentinan intervention showed no significant difference from SA treatment group. Conclusion Lentinan antagonizes SA-induced hepatotoxicity in mice, may be involved in the downregulations of pro-inflammatory OX40 or IL-17A and the activation of anti-oxidative Nrf2, NQO1 signals.

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OX40 expression in neutrophils promotes hepatic ischemia/reperfusion injury

Cited by 19 publications

References 42 publications

Neutrophils undergo switch of apoptosis to NETosis during murine fatty liver injury via S1P receptor 2 signaling

Neutrophils undergo switch of apoptosis to NETosis during murine fatty liver injury via S1P receptor 2 signaling

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Lentinan alleviates arsenic-induced hepatotoxicity in mice via downregulation of OX40/IL-17A and activation of Nrf2 signaling

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