2023
Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation
Arumugam S, Li B, Boodapati S, Nathanson M, Sun B, Ouyang X, Mehal W. Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation. Hepatology 2023, 78: 1448-1461. PMID: 37013923, PMCID: PMC10804318, DOI: 10.1097/hep.0000000000000388.Peer-Reviewed Original ResearchConceptsVoltage-dependent anion channelBioenergetic capacityMitochondrial DNATranscriptional upregulationCyclic GMP-AMP synthaseGMP-AMP synthaseTranscriptional regulationBioenergetic organellesFunctional mitochondriaMitochondrial membraneExternal mitochondrial membraneAnabolic pathwaysMitochondrial massAnion channelInterferon genesHSC transdifferentiationSubsequent activationCGAS-STINGTransdifferentiationIRF3 pathwayPathwaySTING pathwayGenesMitochondriaQuiescent HSCs
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
2012
Sterile Inflammation in the Liver
Kubes P, Mehal WZ. Sterile Inflammation in the Liver. Gastroenterology 2012, 143: 1158-1172. PMID: 22982943, DOI: 10.1053/j.gastro.2012.09.008.Peer-Reviewed Original ResearchMeSH KeywordsAcetaminophenAdenosine TriphosphateCaspase 1Chemical and Drug Induced Liver InjuryChemotaxis, LeukocyteCytokinesFatty LiverFatty Liver, AlcoholicHepatitisHMGB1 ProteinHumansInflammasomesInterleukin-1betaNeutrophilsNon-alcoholic Fatty Liver DiseaseNucleic AcidsReceptors, Pattern RecognitionReperfusion InjurySignal TransductionUric AcidConceptsDamage-associated molecular patternsPattern recognition receptorsImmune cellsSterile inflammationRecognition receptorsCellular pattern recognition receptorsDrug-induced liver injuryEndogenous damage-associated molecular patternsSuch damage-associated molecular patternsMolecular patternsSite of injuryPathogen-associated molecular patternsProtease caspase-1Alcoholic steatohepatitisLiver injuryNonalcoholic steatohepatitisLiver diseaseProinflammatory cytokinesSpecific therapyInterleukin-1βLiver pathologyTissue injuryImmune responseTherapeutic targetActivate receptors
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