المؤلفون: Qu, Xiaoye, Yang, Tao, Wang, Xiao, Xu, Dongwei, Yu, Yeping, Li, Jun, Jiang, Longfeng, Xia, Qiang, Farmer, Douglas, Ke, Bibo

المصدر: JHEP Reports, vol 5, iss 11

مصطلحات موضوعية: ER stress, Foxo1, IRE1α, Innate immunity, Liver inflammation, Necroptosis, Reactive oxygen species, XBP1

الوصف: BACKGROUND & AIMS: Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central player in triggering necroptotic cell death. However, whether macrophage RIPK3 may regulate NOD1-dependent inflammation and calcineurin/transient receptor potential cation channel subfamily M member 7 (TRPM7)-induced hepatocyte death in oxidative stress-induced liver inflammatory injury remains elusive. METHODS: A mouse model of hepatic ischaemia-reperfusion (IR) injury, the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific RIPK3 knockout (RIPK3M-KO) and RIPK3-proficient (RIPK3FL/FL) mice. RESULTS: RIPK3M-KO diminished IR stress-induced liver damage with reduced serum alanine aminotransferase/aspartate aminotransferase levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the RIPK3FL/FL controls. IR stress activated RIPK3, inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α), x-box binding protein 1 (XBP1), nucleotide-binding oligomerisation domain-containing protein 1 (NOD1), NF-κB, forkhead box O1 (Foxo1), calcineurin A, and TRPM7 in ischaemic livers. Conversely, RIPK3M-KO depressed IRE1α, XBP1, NOD1, calcineurin A, and TRPM7 activation with reduced serum tumour necrosis factor α (TNF-α) levels. Moreover, Foxo1M-KO alleviated IR-induced liver injury with reduced NOD1 and TRPM7 expression. Interestingly, chromatin immunoprecipitation coupled with massively parallel sequencing revealed that macrophage Foxo1 colocalised with XBP1 and activated its target gene Zc3h15 (zinc finger CCCH domain-containing protein 15). Activating macrophage XBP1 enhanced Zc3h15, NOD1, and NF-κB activity. However, disruption of macrophage Zc3h15 inhibited NOD1 and hepatocyte calcineurin/TRPM7 activation, with reduced reactive oxygen species production and lactate dehydrogenase release after macrophage/hepatocyte coculture. Furthermore, adoptive transfer of Zc3h15-expressing macrophages in RIPK3M-KO mice augmented IR-triggered liver inflammation and ...

وصف الملف: application/pdf

العلاقة: qt3tb8w9mx; https://escholarship.org/uc/item/3tb8w9mxTest

الإتاحة: https://escholarship.org/uc/item/3tb8w9mxTest

المؤلفون: Qu, Xiaoye, Yang, Tao, Wang, Xiao, Xu, Dongwei, Yu, Yeping, Li, Jun, Jiang, Longfeng, Xia, Qiang, Farmer, Douglas G., Ke, Bibo

المساهمون: National Institutes of Health

المصدر: JHEP Reports ; volume 5, issue 11, page 100879 ; ISSN 2589-5559

مصطلحات موضوعية: Gastroenterology, Hepatology, Immunology and Allergy, Internal Medicine

الإتاحة: https://doi.org/10.1016/j.jhepr.2023.100879Test
https://api.elsevier.com/content/article/PII:S2589555923002100?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2589555923002100?httpAccept=text/plainTest

المؤلفون: Qiu, Tao, Dai, Helong, Guo, Zhiyong, Ke, Bibo, Wei, Qiang

المصدر: Frontiers Research Topics ; ISSN 1664-8714 ; ISBN 9782832508176

الإتاحة: https://doi.org/10.3389/978-2-8325-0817-6Test

المؤلفون: Zhan, Yongqiang, Xu, Dongwei, Tian, Yizhu, Qu, Xiaoye, Sheng, Mingwei, Lin, Yuanbang, Ke, Michael, Jiang, Longfeng, Xia, Qiang, Kaldas, Fady M, Farmer, Douglas G, Ke, Bibo

المصدر: JHEP reports : innovation in hepatology, vol 4, iss 9

مصطلحات موضوعية: ALT, alanine aminotransferase, APAF1, apoptotic peptidase activating factor 1, ASK1, apoptosis signal-regulating kinase 1, AST, aspartate aminotransferase, Apoptosis, BMM, bone marrow-derived macrophage, CXCL-10, C-X-C motif chemokine ligand 10, CYLD, cyclindromatosis, ChIP, chromatin immunoprecipitation, DAMP, damage-associated molecular pattern, DUB, deubiquitinating enzyme, ER, endoplasmic reticulum, ES, embryonic stem, G3BP1, Ras GTPase-activating protein-binding protein 1, GCLC, glutamate-cysteine ligase catalytic subunit, GCLM

الوصف: 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 ...

وصف الملف: application/pdf

العلاقة: qt54g9807f; https://escholarship.org/uc/item/54g9807fTest

الإتاحة: https://escholarship.org/uc/item/54g9807fTest

المؤلفون: Ke, Bibo, Dai, Helong, Wei, Qiang, Guo, Zhiyong, Qiu, Tao

المصدر: Frontiers in Immunology ; volume 13 ; ISSN 1664-3224

الإتاحة: https://doi.org/10.3389/fimmu.2022.1075984Test

المؤلفون: Zhan, Yongqiang, Xu, Dongwei, Tian, Yizhu, Qu, Xiaoye, Sheng, Mingwei, Lin, Yuanbang, Ke, Michael, Jiang, Longfeng, Xia, Qiang, Kaldas, Fady M., Farmer, Douglas G., Ke, Bibo

المساهمون: National Institutes of Health

المصدر: JHEP Reports ; volume 4, issue 9, page 100532 ; ISSN 2589-5559

مصطلحات موضوعية: Gastroenterology, Hepatology, Immunology and Allergy, Internal Medicine

الإتاحة: https://doi.org/10.1016/j.jhepr.2022.100532Test
https://api.elsevier.com/content/article/PII:S2589555922001045?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2589555922001045?httpAccept=text/plainTest

المؤلفون: Sheng, Mingwei, Lin, Yuanbang, Xu, Dongwei, Tian, Yizhu, Zhan, Yongqiang, Li, Changyong, Farmer, Douglas G, Kupiec‐Weglinski, Jerzy W, Ke, Bibo

المصدر: Hepatology, vol 74, iss 3

مصطلحات موضوعية: Regenerative Medicine, Stem Cell Research - Nonembryonic - Non-Human, Digestive Diseases, Stem Cell Research, Liver Disease, Biotechnology, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Inflammatory and immune system, Alanine Transaminase, Animals, CD47 Antigen, Dishevelled Proteins, Hedgehog Proteins, Inflammation, Liver, Macrophages, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Mice, NIMA-Related Kinases, NLR Family, Pyrin Domain-Containing 3 Protein, Receptor, Notch1, Receptors, Immunologic, Reperfusion Injury

الوقت: 1560 - 1577

الوصف: Background and aimsThe cluster ofdifferentiation 47 (CD47)-signal regulatory protein alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury.Approach and resultsIn a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity protein 2), which in turn inhibited NEK7/NLRP3 activity.ConclusionsThe CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory ...

وصف الملف: application/pdf

العلاقة: qt32j9t4g2; https://escholarship.org/uc/item/32j9t4g2Test

الإتاحة: https://escholarship.org/uc/item/32j9t4g2Test

المؤلفون: Xu, Dongwei, Tian, Yizhu, Xia, Qiang, Ke, Bibo

مصطلحات موضوعية: Vaccine Related, HIV/AIDS, Digestive Diseases, Prevention, Emerging Infectious Diseases, Chronic Liver Disease and Cirrhosis, Liver Disease, Infectious Diseases, Hepatitis, Biodefense, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Inflammatory and immune system, Good Health and Well Being, Animals, Cell Transformation, Neoplastic, Disease Susceptibility, Humans, Immunity, Innate, Liver Diseases, Membrane Proteins, Nucleotides, Cyclic, Nucleotidyltransferases, Protein Binding, Protein Transport, Risk Factors

الوصف: Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.

وصف الملف: application/pdf

العلاقة: qt8r28w8n3; https://escholarship.org/uc/item/8r28w8n3Test

الإتاحة: https://escholarship.org/uc/item/8r28w8n3Test

المؤلفون: Li, Changyong, Sheng, Mingwei, Lin, Yuanbang, Xu, Dongwei, Tian, Yizhu, Zhan, Yongqiang, Jiang, Longfeng, Coito, Ana J, Busuttil, Ronald W, Farmer, Douglas G, Kupiec-Weglinski, Jerzy W, Ke, Bibo

المصدر: Cell death and differentiation, vol 28, iss 5

مصطلحات موضوعية: Animals, Humans, Mice, Oxidative Stress, beta Catenin, Hedgehog Proteins, Inflammasomes, Forkhead Box Protein O1, Liver Disease, Digestive Diseases, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology

الوقت: 1705 - 1719

الوصف: Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1M-KO) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1M-KO enhanced β-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1M-KO livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and β-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with β-catenin under inflammatory conditions. Disruption of the Foxo1-β-catenin axis by Foxo1 deletion enhanced β-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1-β-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.

وصف الملف: application/pdf

العلاقة: qt2j12c2n5; https://escholarship.org/uc/item/2j12c2n5Test

الإتاحة: https://escholarship.org/uc/item/2j12c2n5Test

المؤلفون: Xu, Dongwei, Tian, Yizhu, Xia, Qiang, Ke, Bibo

المساهمون: Foundation for the National Institutes of Health

المصدر: Frontiers in Immunology ; volume 12 ; ISSN 1664-3224

الوصف: Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.

الإتاحة: https://doi.org/10.3389/fimmu.2021.682736Test