FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4284967369> ?p ?o ?g. }

• W4284967369 endingPage "100532" @default.
• W4284967369 startingPage "100532" @default.
• W4284967369 abstract "•TXNIP is critical in regulating STING-mediated TBK1 activation and inflammatory responses during oxidative/ER stress.•Macrophage TXNIP deficiency promotes CYLD and activates the NRF2 pathway.•CYLD interacts with NOX4 and regulates NRF2 activation by deubiquitinating NOX4 in macrophages.•NRF2 targets OASL1 and inhibits TBK1-mediated inflammatory responses by regulating G3BP1 activation in macrophages.•OASL1 inhibits stress-induced hepatocyte death via modulating the Apaf1/cytochrome c/caspase-9 pathway. Background & AimsThe stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress.MethodsA mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice.ResultsThe TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2′,5′ oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis.ConclusionsMacrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD–NRF2–OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases.Lay summaryLiver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury. The stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress. A mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice. The TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2′,5′ oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis. Macrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD–NRF2–OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases." @default.
• W4284967369 created "2022-07-10" @default.
• W4284967369 creator A5034436735 @default.
• W4284967369 creator A5039303728 @default.
• W4284967369 creator A5045209569 @default.
• W4284967369 creator A5052607909 @default.
• W4284967369 creator A5061977944 @default.
• W4284967369 creator A5067220739 @default.
• W4284967369 creator A5068321792 @default.
• W4284967369 creator A5072821864 @default.
• W4284967369 creator A5079724026 @default.
• W4284967369 creator A5080668711 @default.
• W4284967369 creator A5082984382 @default.
• W4284967369 creator A5085075008 @default.
• W4284967369 date "2022-09-01" @default.
• W4284967369 modified "2023-10-14" @default.
• W4284967369 title "Novel role of macrophage TXNIP-mediated CYLD–NRF2–OASL1 axis in stress-induced liver inflammation and cell death" @default.
• W4284967369 cites W1548775239 @default.
• W4284967369 cites W162447880 @default.
• W4284967369 cites W1923914039 @default.
• W4284967369 cites W1966625828 @default.
• W4284967369 cites W1975915247 @default.
• W4284967369 cites W1995177733 @default.
• W4284967369 cites W1995762247 @default.
• W4284967369 cites W1997146393 @default.
• W4284967369 cites W2004267808 @default.
• W4284967369 cites W2006406228 @default.
• W4284967369 cites W2008258524 @default.
• W4284967369 cites W2009931987 @default.
• W4284967369 cites W2018607502 @default.
• W4284967369 cites W2037658687 @default.
• W4284967369 cites W2060004514 @default.
• W4284967369 cites W2066538173 @default.
• W4284967369 cites W2067913123 @default.
• W4284967369 cites W2069310363 @default.
• W4284967369 cites W2074171762 @default.
• W4284967369 cites W2092842081 @default.
• W4284967369 cites W2102379760 @default.
• W4284967369 cites W2103059173 @default.
• W4284967369 cites W2111711854 @default.
• W4284967369 cites W2114727688 @default.
• W4284967369 cites W2119517665 @default.
• W4284967369 cites W2130888824 @default.
• W4284967369 cites W2144787399 @default.
• W4284967369 cites W2155135949 @default.
• W4284967369 cites W2159156984 @default.
• W4284967369 cites W2325707043 @default.
• W4284967369 cites W2508450008 @default.
• W4284967369 cites W2519786994 @default.
• W4284967369 cites W2560479095 @default.
• W4284967369 cites W2610633818 @default.
• W4284967369 cites W2614085889 @default.
• W4284967369 cites W2620241325 @default.
• W4284967369 cites W2753995352 @default.
• W4284967369 cites W2763591845 @default.
• W4284967369 cites W2778677617 @default.
• W4284967369 cites W2780227486 @default.
• W4284967369 cites W2808253760 @default.
• W4284967369 cites W2891103014 @default.
• W4284967369 cites W2894672650 @default.
• W4284967369 cites W2901337826 @default.
• W4284967369 cites W2905091095 @default.
• W4284967369 cites W3010750792 @default.
• W4284967369 cites W3024191006 @default.
• W4284967369 cites W3112571846 @default.
• W4284967369 cites W3151167688 @default.
• W4284967369 cites W3159586444 @default.
• W4284967369 cites W3159813479 @default.
• W4284967369 doi "https://doi.org/10.1016/j.jhepr.2022.100532" @default.
• W4284967369 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36035360" @default.
• W4284967369 hasPublicationYear "2022" @default.
• W4284967369 type Work @default.
• W4284967369 citedByCount "10" @default.
• W4284967369 countsByYear W42849673692022 @default.
• W4284967369 countsByYear W42849673692023 @default.
• W4284967369 crossrefType "journal-article" @default.
• W4284967369 hasAuthorship W4284967369A5034436735 @default.
• W4284967369 hasAuthorship W4284967369A5039303728 @default.
• W4284967369 hasAuthorship W4284967369A5045209569 @default.
• W4284967369 hasAuthorship W4284967369A5052607909 @default.
• W4284967369 hasAuthorship W4284967369A5061977944 @default.
• W4284967369 hasAuthorship W4284967369A5067220739 @default.
• W4284967369 hasAuthorship W4284967369A5068321792 @default.
• W4284967369 hasAuthorship W4284967369A5072821864 @default.
• W4284967369 hasAuthorship W4284967369A5079724026 @default.
• W4284967369 hasAuthorship W4284967369A5080668711 @default.
• W4284967369 hasAuthorship W4284967369A5082984382 @default.
• W4284967369 hasAuthorship W4284967369A5085075008 @default.
• W4284967369 hasBestOaLocation W42849673693 @default.
• W4284967369 hasConcept C134018914 @default.
• W4284967369 hasConcept C139447449 @default.
• W4284967369 hasConcept C158617107 @default.
• W4284967369 hasConcept C185592680 @default.
• W4284967369 hasConcept C203014093 @default.
• W4284967369 hasConcept C2776151105 @default.
• W4284967369 hasConcept C2776914184 @default.
• W4284967369 hasConcept C2779076967 @default.
• W4284967369 hasConcept C3623737 @default.

• next