Liver kinase B1 attenuates liver ischemia/reperfusion injury via inhibiting the NLRP3 inflammasome

Dai, Jiangwen; Chen, Qingsong; Huang, Weifeng; Shi, Kun; Zhang, Yuke; Li, Tingting; Mou, Tong; Huang, Zuotian; Wu, Zhongjun

doi:10.1093/abbs/gmab030

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…[14] Previous findings also confirmed that the NLRP3 inflammasome is activated in H/R-stimulated RAW264.7 cells. [15,36] HDAC6 inhibition is therefore required to reduce excessive downstream inflammatory responses. The HDAC6-specific inhibitor, TubA, can be used to treat HS [20,37,38] and inhibit NLRP3 inflammasome activation.…”

Section: Discussionmentioning

confidence: 99%

Effect of tubastatin A on NLRP3 inflammasome activation in macrophages under hypoxia/reoxygenation conditions

Li,

Liu,

Cui

et al. 2024

World Journal of Emergency Medicine

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BACKGROUND: There are currently no effective drugs to mitigate the ischemia/reperfusion injury caused by fluid resuscitation after hemorrhagic shock (HS). The aim of this study was to explore the potential of the histone deacetylase 6 (HDAC6)-specific inhibitor tubastatin A (TubA) to suppress nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation in macrophages under hypoxia/reoxygenation (H/R) conditions. METHODS:The viability of RAW264.7 cells subjected to H/R after treatment with different concentrations of TubA was assessed using a cell-counting kit-8 (CCK8) assay. Briefly, 2.5 µmol/L TubA was used with RAW264.7 cells under H/R condition. RAW264.7 cells were divided into three groups, namely the control, H/R, and TubA groups. The levels of reactive oxygen species (ROS) in the cells were detected using fluorescence microscopy. The protein expression of HDAC6, heat shock protein 90 (Hsp90), inducible nitric oxide synthase (iNOS), NLRP3, gasdermin-D (GSDMD), Caspase-1, GSDMD-N, and Caspase-1 p20 was detected by western blotting. The levels of interleukin-1β (IL-1β) and IL-18 in the supernatants were detected using enzyme-linked immunosorbent assay (ELISA).RESULTS: HDAC6, Hsp90, and iNOS expression levels were significantly higher (P<0.01) in the H/R group than in the control group, but lower (P<0.05) in the TubA group than in the H/R group. When comparing the H/R group to the control group, ROS levels were significantly higher (P<0.01), but significantly reduced (P<0.05) in the TubA group. The H/R group had higher NLRP3, GSDMD, Caspase-1, GSDMD-N, and Caspase-1 p20 expression levels than the control group (P<0.05), however the TubA group had significantly lower expression levels than the H/R group (P<0.05). L-1β and IL-18 levels in the supernatants were significantly higher in the H/R group compared to the control group (P<0.01), but significantly lower in the TubA group compared to the H/R group (P<0.01).CONCLUSION: TubA inhibited the expression of HDAC6, Hsp90, and iNOS in macrophages subjected to H/R. This inhibition led to a decrease in the content of ROS in cells, which subsequently inhibited the activation of the NLRP3 inflammasome and the secretion of IL-1β and IL-18.

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Section: Discussionmentioning

confidence: 99%

Effect of tubastatin A on NLRP3 inflammasome activation in macrophages under hypoxia/reoxygenation conditions

Li,

Liu,

Cui

et al. 2024

World Journal of Emergency Medicine

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“…Serum cytokines, including TNF-α, IL-1β, and IL-6, were measured using their corresponding enzyme-linked immunosorbent assay kits (Beyotime) as reported in our previous studies [ 27 , 28 ] . According to the instructions, the kits were prepared in advance and left at room temperature for 15 min.…”

Section: Methodsmentioning

confidence: 99%

“…Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were monitored using a commercial microplate kit (JianCheng Bioengineering Institute, Nanjing, China) as reported in our previous studies [ 27 , 28 ] . After the reaction, NaOH was added and incubated at room temperature for 10 min.…”

Section: Methodsmentioning

confidence: 99%

DUSP9 alleviates hepatic ischemia/reperfusion injury by restraining both mitogen-activated protein kinase and IKK in an apoptosis signal-regulating kinase 1-dependent manner

Li¹,

Huang²,

Luo³

et al. 2022

ABBS

Self Cite

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Hepatic ischemia/reperfusion (I/R) injury occurs frequently in various liver operations and diseases, but its effective treatment remains inadequate because the key switch that leads to hepatic explosive inflammation has not been well disclosed. Dual specificity phosphatase 9 (DUSP9) is widely involved in the innate immune response of solid organs and is sometimes regulated by ubiquitin. In the present study, we find that DUSP9 is reduced in mouse hepatic I/R injury. DUSP9 enrichment attenuates hepatic inflammation both in vivo and in vitro as revealed by western blot analysis and qRT-PCR. In contrast, DUSP9 depletion leads to more severe I/R injury. Mechanistically, DUSP9 inhibits the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) by directly binding to ASK1, thereby decreasing tumor necrosis factor receptor-associated factor 6 (TRAF6), K63 ubiquitin and the phosphorylation of p38/JNK1 instead of ERK1. The present study documents a novel role of DUSP9 in hepatic I/R injury and implies the potential of targeting the DUSP9/ASK1 axis towards mitogen-activated protein kinase and TRAF6/inhibitor of κB kinase pathways.

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“…Therefore, the cooperation between non-TLR molecules and the inflammasome pathway could be an attractive target for clinical intervention. This was addressed when high expression of liver kinase B1 (LKB1) correlated with decreased expression of the NLRP3 inflammasome via upregulation of FoxO1 and deactivation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation [20]. Another group investigated the relationship between non-TLRs and TLRs and showed that modulation of TLR2, NOD1, and NOD2 led to decreased neutrophil infiltration in ischemic kidneys [21].…”

Section: The Intrinsic Relationship Between Nucleotide-binding Domain...mentioning

confidence: 99%

New insights into ischemia-reperfusion injury signaling pathways in organ transplantation

Dery

Kupiec‐Weglinski

2022

Current Opinion in Organ Transplantation

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Purpose of reviewIschemia-reperfusion injury (IRI) leading to allograft rejection in solid organ transplant recipients is a devastating event that compromises graft and patient survival. As our clinical knowledge regarding its definition and presentation has significantly improved over the last years, adequate biomarkers translating to important therapeutic intervention remains a challenge. This review will summarize recent findings in this area.Recent findingsIn the past 18 months, our understanding of organ transplantation IRI has improved. IRI involves a positive amplification feedback loop encompassing damaged cells at the graft site, the activity of redox-sensitive damage-associated molecular patterns, and local sequestration of recipient-derived monocytes, lymphocytes and polymorphonuclear leukocytes, like neutrophils, to sustain the immunological cascade and to enhance the destruction of the foreign tissue. Recent studies have identified critical components leading to IRI, including the oxidation state of high mobility group box 1, a classic danger signal, its role in the Toll-like receptor 4–interleukin (IL)-23–IL-17A signaling axis, and the role of neutrophils and CD321, a marker for transmigration of circulating leukocytes into the inflamed tissue. In addition, recent findings imply that the protective functions mediated by autophagy activation counterbalance the detrimental nucleotide-binding domain-like receptor family, pyrin domain containing 3 inflammasome pathway. Finally, clinical studies reveal the posttransplant variables associated with early allograft dysfunction and IRI.SummaryThe future challenge will be understanding how crosstalk at the molecular and cellular levels integrate prospectively to predict which peri-transplant signals are essential for long-term clinical outcomes.

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Liver kinase B1 attenuates liver ischemia/reperfusion injury via inhibiting the NLRP3 inflammasome

Cited by 7 publications

References 38 publications

Effect of tubastatin A on NLRP3 inflammasome activation in macrophages under hypoxia/reoxygenation conditions

Effect of tubastatin A on NLRP3 inflammasome activation in macrophages under hypoxia/reoxygenation conditions

DUSP9 alleviates hepatic ischemia/reperfusion injury by restraining both mitogen-activated protein kinase and IKK in an apoptosis signal-regulating kinase 1-dependent manner

New insights into ischemia-reperfusion injury signaling pathways in organ transplantation

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