VX765, a Specific Caspase-1 Inhibitor, Alleviates Lung Ischemia Reperfusion Injury by Suppressing Endothelial Pyroptosis and Barrier Dysfunction

Wu, Siyi; Zhao, Li; Ye, Mengling; Liu, Chunxia; Líu, Hao; He, Xiaojing; Qin, Yi; Liang, Fu-Wen; Pan, Linghui; Lin, Fei

doi:10.1155/2021/4525988

Cited by 18 publications

(9 citation statements)

References 38 publications

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“…Moreover, assembly of NLRP3 inflammasome with caspase-1 or 11 mediated canonical inflammasomes or not [ 28 , 29 ]. To determine the IL-1β secretion mechanisms in PMs induced by A. caviae , PMs were first pretreated withVX765, a caspase-1 specific inhibitor [ 30 ], before A. caviae infection, and measured the NLRP3 inflammasome biomarkers. The results showed that caspase-1 in V X 765 pretreatment group was inhibited obviously ( P < 0.01) ( Figures 4(a,b) ), but there was no obvious change in pro-caspase-1 ( Figure 4c ).…”

Section: Resultsmentioning

confidence: 99%

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A. caviae infection triggers IL-1β secretion through activating NLRP3 inflammasome mediated by NF-κB signaling pathway partly in a TLR2 dependent manner

et al. 2022

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Aeromonas caviae , an important food-borne pathogen, induces serious invasive infections and inflammation. The pro-inflammatory IL-1β functions against pathogenic infections and is elevated in various Aeromonas infection cases. However, the molecular mechanism of A. caviae -mediated IL-1β secretion remains unknown. In this study, mouse macrophages (PMs) were used to establish A. caviae infection model and multiple strategies were utilized to explore the mechanism of IL-1β secretion. IL-1β was elevated in A. caviae infected murine serum, PMs lysates or supernatants. This process triggered NLRP3 levels upregulation, ASC oligomerization, as well as dot gathering of NLRP3 and speck-like signals of ASC in the cytoplasm. MCC950 blocked A. caviae mediated IL-1β release. Meanwhile, NLRP3 inflammasome mediated the release of IL-1β in dose- and time-dependent manners, and the release of IL-1β was dependent on active caspase-1, as well as NLRP3 inflammasome was activated by potassium efflux and cathepsin B release ways. A. caviae also enhanced TLR2 levels, and deletion of TLR2 obviously decreased IL-1β secretion. What’s more, A. caviae resulted in NF-κB p65 nuclear translocation partly in a TLR2-dependent manner. Blocking NF-κB using BAY 11-7082 almost completely inhibited NLRP3 inflammasome first signal pro-IL-1β expression. Blocking TLR2, NF-κB, NLRP3 inflammasome significantly downregulated IL-1β release and TNF-α and IL-6 levels. These data illustrate that A. caviae caused IL-1β secretion in PMs is controlled by NLRP3 inflammasome, of which is mediated by NF-κB pathway and is partially dependent on TLR2, providing basis for drugs against A. caviae .

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Section: Resultsmentioning

confidence: 99%

“…Assembly of NLRP3 inflammasome is mediated by canonical or non-canonical ways in Gram-negative bacteria infection [ 50 ]. V × 765 specially blocked caspase-1 [ 30 , 51 ]. Pre-treatment of V × 765 diminished active caspase and IL-1β.…”

Section: Discussionmentioning

confidence: 99%

A. caviae infection triggers IL-1β secretion through activating NLRP3 inflammasome mediated by NF-κB signaling pathway partly in a TLR2 dependent manner

et al. 2022

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“…Breaking out of this pathogenic cycle could represent an important building block to reduce non-AIDS related morbidities caused by persisting inflammation during cART (57). To date, despite increased therapeutic interests (45)(46)(47), no compound targeting the inflammasome was marketed (58). Nevertheless, The caspase 1 inhibitor VX-765 was approved by the Food and Drug Administration for human clinical trials, showed a good safety profile, and represents currently a promising drug to prevent the onset of inflammation in several diseases (47).…”

Section: Discussionmentioning

confidence: 99%

“…Altogether, these results strongly suggest that inflammasome activation occurs early during HIV-1 infection, and could be a central mechanism in the early viral escape to the immune system and furthermore, may facilitate the establishment of the pathogenic cycle of HIV-1 reservoirs persistence and inflammation. VX-765, a selective caspase 1 inhibitor, reduces activation and activity of caspase 1 and antagonize NLRP3 inflammasome assembly and activation in the context of several inflammatory disorders or diseases such as atheroschlerosis, sepsis, or alzheimer disease (45)(46)(47). Therefore, the aim of our study was to investigate the effects of the Caspase-1 inhibitor VX-765 in an humanized mouse model of HIV-1 infection as a therapeutic strategy to reduce HIV-1 induced inflammation and reservoirs establishment.…”

Section: Introductionmentioning

confidence: 99%

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4⁺T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

Amand

Adams

Schober

et al. 2022

Preprint

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Background: HIV-1 infection results in the activation of inflammasome involving NLRP3, IFI16, caspase-1 and release of IL-1β and IL-18. Early inflammasome activation may facilitate viral spread and establishment of the viral reservoir. We evaluated the effect of the caspase-1 inhibitor VX-765 on virological and immunological parameters after HIV-1 infection in humanized mice. Methods: NSG mice were engrafted with human CD34+ hematopoietic stem cells and were infected with HIV-1 JRCSF. 15 mice were first sacrificed serially to investigate kinetics of the HIV-1 related inflammasome activation. Infected mice (n=24) were then treated with VX-765 or vehicle from day 1 post infection for 21 days. Blood and organs were collected at different time points, and analysed for inflammasome genes expression, cytokines levels, viral load, CD4 cell count, and total HIV-1 DNA. Results: Expression of caspase-1, NLRP3 and IL1-β was increased in lymph nodes and bone marrow on day 1 and 3 post infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p< 0.001 respectively between day 1 and 3). IFI16 expression peaked at day 24 in lymph node and bone marrow (FC 1.49 and 1.64, p<0.05) and coincides with increased IL-18 levels in plasma (6.89 vs. 83.19 pg/ml, p=0.004). AIM2 and IFI16 expression correlated with increased viral load in tissues (p<0.005 for the spleen) and loss of CD4+ T cells percentage in blood (p<0.0001 for the spleen). Treatment with VX-765 significantly reduced TNF-α at day 11 (0.47 vs. 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4 + T cells (44.3% vs 36,7%, p=0.01) and the CD4/CD8 ratio (0.92 vs 0.67, p=0.005) in plasma. Importantly, viral load (4.26 vs. 4.89 log 10 copies/ml, p=0.027) and total HIV-1 DNA (1 054 vs. 2 889 copies /106 cells, p=0.029) were decreased in VX-765-treated mice as compared to vehicle-treated mice. Discussion: we report here an early inflammasome activation before detectable viral dissemination in humanized mice. We demonstrated that targeting inflammasome activation early after HIV-1 infection may represent a potential therapeutic strategy to prevent CD4+ T cell depletion as well as to reduce immune activation, viral load and the HIV-1 reservoir formation.

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“… 9 LIRI could be attenuated by suppressing selective NLRP3 inflammasome and pyroptosis. 14 , 15 Thus, inhibition of NLRP3 inflammasome and pyroptosis is beneficial to alleviate LIRI.…”

Section: Introductionmentioning

confidence: 99%

Emodin alleviates lung ischemia–reperfusion injury by suppressing gasdermin D‐mediated pyroptosis in rats

Jin¹,

Zhou³

et al. 2023

Clinical Respiratory J

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Background Pyroptosis refers to programmed cell death associated with inflammation. Emodin has been reported to alleviate lung injuries caused by various pathological processes and attenuate ischemia–reperfusion (I/R) injuries in diverse tissues. Methods Lewis rats were assigned into the sham, the I/R, and the I/R + emodin groups. Emodin and phosphate‐buffered saline were intraperitoneally injected into rats of the emodin group and I/R group for 30 min, respectively. These rats were then subjected to left thoracotomy followed by 90‐min clamping of the left hilum and 120‐min reperfusion. Sham‐operated rats underwent 210‐min ventilation. Lung functions, histological changes, lung edema, and cytokine levels were assessed. Protein levels were measured by western blotting. Immunofluorescence staining was conducted to evaluate pyroptosis. Results Emodin alleviated the I/R‐induced lung dysfunction, lung damages, and inflammation. Protective effects of emodin against I/R‐mediated endothelial pyroptosis was observed in vivo and in vitro. Mechanistically, emodin inactivated the TLR4/MyD88/NF‐κB/NLRP3 pathway. Conclusion Emodin attenuates lung ischemia–reperfusion injury by inhibiting GSDMD‐mediated pyroptosis in rats.

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VX765, a Specific Caspase-1 Inhibitor, Alleviates Lung Ischemia Reperfusion Injury by Suppressing Endothelial Pyroptosis and Barrier Dysfunction

Cited by 18 publications

References 38 publications

A. caviae infection triggers IL-1β secretion through activating NLRP3 inflammasome mediated by NF-κB signaling pathway partly in a TLR2 dependent manner

A. caviae infection triggers IL-1β secretion through activating NLRP3 inflammasome mediated by NF-κB signaling pathway partly in a TLR2 dependent manner

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4⁺T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

Emodin alleviates lung ischemia–reperfusion injury by suppressing gasdermin D‐mediated pyroptosis in rats

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VX765, a Specific Caspase-1 Inhibitor, Alleviates Lung Ischemia Reperfusion Injury by Suppressing Endothelial Pyroptosis and Barrier Dysfunction

Cited by 18 publications

References 38 publications

A. caviae infection triggers IL-1β secretion through activating NLRP3 inflammasome mediated by NF-κB signaling pathway partly in a TLR2 dependent manner

A. caviae infection triggers IL-1β secretion through activating NLRP3 inflammasome mediated by NF-κB signaling pathway partly in a TLR2 dependent manner

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

Emodin alleviates lung ischemia–reperfusion injury by suppressing gasdermin D‐mediated pyroptosis in rats

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The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4⁺T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice