2023
Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions
Kaffe E, Roulis M, Zhao J, Qu R, Sefik E, Mirza H, Zhou J, Zheng Y, Charkoftaki G, Vasiliou V, Vatner D, Mehal W, AlcHepNet, Kluger Y, Flavell R. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell 2023, 186: 3793-3809.e26. PMID: 37562401, PMCID: PMC10544749, DOI: 10.1016/j.cell.2023.07.017.Peer-Reviewed Original ResearchConceptsMetabolic functionsSpecies-specific interactionsKey metabolic functionsCell-autonomous mechanismsNon-alcoholic fatty liver diseaseMajor metabolic hubNon-parenchymal cellsMetabolic hubHuman hepatocytesMicroenvironmental regulationHuman diseasesHuman-specific aspectsHuman pathologiesHomeostatic processesSpecies mismatchCholesterol uptakeFatty liver diseaseParacrine mannerHuman immuneBile acid conjugationSinusoidal endothelial cellsHepatic metabolic functionMouse liverEndothelial cellsCells
2019
Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9
Vijay G, Hu C, Peng J, Garcia-Martinez I, Hoque R, Verghis RM, Ma Y, Mehal W, Shawcross DL, Wen L. Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9. Cellular And Molecular Gastroenterology And Hepatology 2019, 8: 609-623. PMID: 31401214, PMCID: PMC6889059, DOI: 10.1016/j.jcmgh.2019.08.002.Peer-Reviewed Original ResearchConceptsAcute liver failureT cell cytokine productionBrain edemaCell cytokine productionCytokine productionT cell expressionBrain waterIntracranial hypertensionTotal plasma DNAFl/AC injectionAcetaminophen-induced acute liver failureAmmonia-induced brain edemaCell expressionToll-like receptor 9Intracellular cytokine productionLymphocyte cytokine productionMacrophage cytokine productionSystemic inflammationImmune dysfunctionLiver failureTLR9 expressionWT miceReceptor 9T cells
2018
Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
Ouyang X, Han SN, Zhang JY, Dioletis E, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Stärkel P, Caballeria J, Pongratz RL, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Garcia-Martinez I, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ. Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. Cell Metabolism 2018, 27: 339-350.e3. PMID: 29414684, PMCID: PMC5806149, DOI: 10.1016/j.cmet.2018.01.007.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell NucleusChromatinDigoxinDisease Models, AnimalEndotoxinsHistonesHumansHypoxia-Inducible Factor 1, alpha SubunitInflammationLiverNon-alcoholic Fatty Liver DiseaseOxidation-ReductionProtein BindingPyruvate KinaseTHP-1 CellsTranscription, GeneticTranscriptional ActivationConceptsHIF-1α transactivationSterile inflammationHIF-1α pathway activationNon-alcoholic steatohepatitisKinase M2Major clinical consequencesAbility of digoxinLiver inflammationLiver diseasePyruvate kinase M2Clinical consequencesTherapeutic targetInflammationTissue damageHIF-1αPathway activationDigoxinOxidative stressCardiac glycosidesSteatohepatitisDigoxin bindsNovel roleLiverUbiquitous responseActivation
2014
Lactate Reduces Liver and Pancreatic Injury in Toll-Like Receptor– and Inflammasome-Mediated Inflammation via GPR81-Mediated Suppression of Innate Immunity
Hoque R, Farooq A, Ghani A, Gorelick F, Mehal WZ. Lactate Reduces Liver and Pancreatic Injury in Toll-Like Receptor– and Inflammasome-Mediated Inflammation via GPR81-Mediated Suppression of Innate Immunity. Gastroenterology 2014, 146: 1763-1774. PMID: 24657625, PMCID: PMC4104305, DOI: 10.1053/j.gastro.2014.03.014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Inflammatory AgentsArrestinsBeta-Arrestin 2Beta-ArrestinsCarrier ProteinsCell LineCeruletideChemical and Drug Induced Liver InjuryCytoprotectionDisease Models, AnimalDose-Response Relationship, DrugDown-RegulationGalactosamineHumansImmunity, InnateInflammasomesInjections, IntraperitonealInterleukin-1betaLipopolysaccharidesLiverMacrophagesMaleMiceMice, Inbred C57BLMonocytesNF-kappa BNLR Family, Pyrin Domain-Containing 3 ProteinPancreasPancreatitisReceptors, G-Protein-CoupledRNA InterferenceRNA, Small InterferingSignal TransductionSodium LactateToll-Like Receptor 4Toll-Like ReceptorsTransfectionConceptsToll-like receptorsRelease of IL1βAdministration of lipopolysaccharideOrgan injuryNF-κBCaspase-1TLR inductionAcute pancreatitisPyrin domain-containing protein 3Administration of lactatePromising immunomodulatory therapyAcute liver injuryAcute organ injuryMacrophages of miceDomain-containing protein 3Production of IL1βRAW 264.7 cellsConcentration of lactateAcute hepatitisImmunomodulatory therapyImmune hepatitisPancreatic injuryLactate receptorLiver injuryNLRP3 inflammasome
2013
Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway
Ouyang X, Ghani A, Malik A, Wilder T, Colegio OR, Flavell RA, Cronstein BN, Mehal WZ. Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway. Nature Communications 2013, 4: 2909. PMID: 24352507, PMCID: PMC3895487, DOI: 10.1038/ncomms3909.Peer-Reviewed Original ResearchMeSH KeywordsAdenosineAdenosine TriphosphateAnimalsCarrier ProteinsCyclic AMPCyclic AMP Response Element-Binding ProteinCyclic AMP-Dependent Protein KinasesHypoxia-Inducible Factor 1, alpha SubunitInflammasomesInterleukin-1betaLipopolysaccharidesLiverMacrophagesMaleMiceMice, Inbred C57BLNLR Family, Pyrin Domain-Containing 3 ProteinReceptor, Adenosine A2ASignal TransductionConceptsHIF-1α pathwayInflammasome activityInflammasome activationA2A receptorsIL-1β productionIL-1β responseReceptor-mediated signalingLack of responseTolerogenic stateChronic diseasesInflammatory responseInflammasome pathwayPrevious exposureLipopolysaccharideAdenosineReceptorsActivationKey regulatorInitial activationPathwaySignalingResponseInterleukinStimuliDisease
2010
Cell Death and Fibrogenesis
Mehal W, Imaeda A. Cell Death and Fibrogenesis. Seminars In Liver Disease 2010, 30: 226-231. PMID: 20665375, PMCID: PMC3219753, DOI: 10.1055/s-0030-1255352.BooksConceptsHepatic stellate cellsQuiescent hepatic stellate cellsChronic liver injuryNatural killer cellsCell deathHIV infectionLiver injuryNK cellsKiller cellsAntifibrotic effectsImmune suppressionImmune cellsProfibrotic effectsStellate cellsHepatocyte deathHSC apoptosisDeathCellular deathFibrosisCellular debrisMatrix depositionHSC deathSurvival signalsApoptotic bodiesProapoptotic signals
2009
Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome
Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS, Flavell RA, Mehal WZ. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. Journal Of Clinical Investigation 2009, 119: 305-314. PMID: 19164858, PMCID: PMC2631294, DOI: 10.1172/jci35958.Peer-Reviewed Original ResearchMeSH KeywordsAcetaminophenAnalgesics, Non-NarcoticAnimalsApoptosisAspirinCarrier ProteinsCaspase InhibitorsCell LineCyclooxygenase InhibitorsDose-Response Relationship, DrugHumansImmunity, InnateInflammationInterleukin-18Interleukin-1betaLiverMiceMice, Inbred C57BLNLR Family, Pyrin Domain-Containing 3 ProteinSignal TransductionToll-Like Receptor 9ConceptsLiver injuryIL-1betaNALP3 inflammasomeHepatocyte deathAcetaminophen-induced liver injuryCaspase-1Proinflammatory cytokine activationInnate immune activationSterile inflammatory responseType of injuryCOX-1 inhibitionMature IL-1betaPotential therapeutic approachSinusoidal endothelial cellsOverall tissue injuryIL-18Immune activationProinflammatory cytokinesTLR9 antagonistInitial insultInflammatory responseTissue injuryProtective effectCytokine activationTherapeutic approaches
2001
Antigen Presentation by Liver Cells Controls Intrahepatic T Cell Trapping, Whereas Bone Marrow-Derived Cells Preferentially Promote Intrahepatic T Cell Apoptosis
Mehal W, Azzaroli F, Crispe I. Antigen Presentation by Liver Cells Controls Intrahepatic T Cell Trapping, Whereas Bone Marrow-Derived Cells Preferentially Promote Intrahepatic T Cell Apoptosis. The Journal Of Immunology 2001, 167: 667-673. PMID: 11441069, DOI: 10.4049/jimmunol.167.2.667.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationApoptosisBone Marrow CellsBone Marrow TransplantationCD8-Positive T-LymphocytesCell MovementCells, CulturedCytotoxicity, ImmunologicLiverLymphocyte ActivationLymphocyte CountLymphocyte DepletionMiceMice, Inbred C57BLMice, TransgenicRadiation ChimeraSpleenStem Cell TransplantationStem CellsConceptsMarrow-derived cellsNon-bone marrow-derived cellsT cellsT cell apoptosisAg presentationLiver injuryBone marrow-derived cellsCell apoptosisSuch liver injuryT cell trappingT cell accumulationBone marrow chimerasTCR transgenic miceT cell populationsT cell deletionAdoptive transferIntrahepatic accumulationLiver damageHepatocyte damageSystemic activationAntigen presentationBone marrowCell accumulationClonal expansionCell deletionInvolvement of CD1 in Peripheral Deletion of T Lymphocytes Is Independent of NK T Cells
Dao T, Exley M, Mehal W, Tahir S, Snapper S, Taniguchi M, Balk S, Crispe I. Involvement of CD1 in Peripheral Deletion of T Lymphocytes Is Independent of NK T Cells. The Journal Of Immunology 2001, 166: 3090-3097. PMID: 11207260, DOI: 10.4049/jimmunol.166.5.3090.Peer-Reviewed Original ResearchConceptsNK T cellsPeripheral T cell deletionT cell deletionT cellsCell deletionCD1-deficient miceBone marrow chimerasExpression of CD1T cell activationMHC-like moleculesNonlymphoid organsLymph nodesPeripheral deletionNormal miceT lymphocytesCell activationMutant mouse linesMouse linesAttenuated accumulationMiceLymphocytesNovel roleCD1Ab resultsLiverImmunology of the healthy liver: Old questions and new insights
Mehal W, Azzaroli F, Crispe I. Immunology of the healthy liver: Old questions and new insights. Gastroenterology 2001, 120: 250-260. PMID: 11208734, DOI: 10.1053/gast.2001.20947.Peer-Reviewed Original Research
2000
The liver as a site of T‐cell apoptosis: graveyard, or killing field?
Crispe I, Dao T, Klugewitz K, Mehal W, Metz D. The liver as a site of T‐cell apoptosis: graveyard, or killing field? Immunological Reviews 2000, 174: 47-62. PMID: 10807506, DOI: 10.1034/j.1600-0528.2002.017412.x.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntigensApoptosisCD8-Positive T-LymphocytesCell AdhesionEndothelium, VascularFas ReceptorHepatitis CHumansImmune ToleranceImmunophenotypingIntestinal AbsorptionKiller Cells, NaturalKupffer CellsLiverLiver CirculationLiver TransplantationLymphocyte ActivationLymphocyte SubsetsMiceMice, TransgenicModels, ImmunologicalPortal VeinConceptsT cellsNatural killerT cell trappingNK T cellsPeripheral immune responsePortal vein infusionApoptotic T cellsT cell apoptosisNormal mouse liverPhenomenon of toleranceApoptotic CD8Liver allograftsOral toleranceHepatitis C.Lymphocyte populationsAntigenic cellsImmune responseLiver pathogensVein infusionClearance phaseLiver resultsLiverDirect perfusionMouse liverCell populations
1999
Selective retention of activated CD8+ T cells by the normal liver.
Mehal W, Juedes A, Crispe I. Selective retention of activated CD8+ T cells by the normal liver. The Journal Of Immunology 1999, 163: 3202-10. PMID: 10477588, DOI: 10.4049/jimmunol.163.6.3202.Peer-Reviewed Original Research
1998
IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells.
Dao T, Mehal W, Crispe I. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. The Journal Of Immunology 1998, 161: 2217-22. PMID: 9725214, DOI: 10.4049/jimmunol.161.5.2217.Peer-Reviewed Original ResearchMeSH KeywordsAdjuvants, ImmunologicAnimalsCytokinesCytotoxicity, ImmunologicHumansInterferon InducersInterferon-gammaInterleukin-18Jurkat CellsKiller Cells, NaturalLiverLymphoproliferative DisordersMembrane GlycoproteinsMiceMice, Inbred C57BLMice, Inbred StrainsMice, KnockoutPerforinPore Forming Cytotoxic ProteinsT-Lymphocyte SubsetsT-Lymphocytes, CytotoxicTumor Necrosis Factor-alphaConceptsNK T cellsLiver NK T cellsIL-18NK cellsIntrahepatic lymphocyte subpopulationsNK cell activityPerforin-dependent cytotoxicityPerforin-dependent pathwayTNF-alpha productionSoluble TNF-alphaT cell linesLymphocyte subpopulationsCytotoxic cellsTNF-alphaT cellsCell activityExact mechanismNKCell populationsCell linesLiverCytotoxicityCellsCytokinesCTLTCR ligation on CD8+ T cells creates double-negative cells in vivo.
Mehal W, Crispe I. TCR ligation on CD8+ T cells creates double-negative cells in vivo. The Journal Of Immunology 1998, 161: 1686-93. PMID: 9712032, DOI: 10.4049/jimmunol.161.4.1686.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, Polyomavirus TransformingCD8-Positive T-LymphocytesClonal DeletionFas ReceptorHistocompatibility Antigens Class IImmunophenotypingInjections, IntraperitonealLiverLymph NodesLymphocyte CountLymphocyte DepletionMiceMice, Inbred C57BLMice, Inbred MRL lprMice, TransgenicReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte Subsets
1996
Strange brew: T cells in the liver
Crispe I, Mehal W. Strange brew: T cells in the liver. Trends In Immunology 1996, 17: 522-525. PMID: 8961629, DOI: 10.1016/s0167-5699(96)80906-6.Peer-Reviewed Original Research