Featured Publications
A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells
Axisa P, Yoshida T, Lucca L, Kasler H, Lincoln M, Pham G, Del Priore D, Carpier J, Lucas C, Verdin E, Sumida T, Hafler D. A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells. Science Translational Medicine 2022, 14: eabl3651. PMID: 36516268, DOI: 10.1126/scitranslmed.abl3651.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalitisRegulatory T cellsHistone deacetylase 7Multiple sclerosisT cellsMouse modelFunction of Foxp3CD4 T cellsHigher suppressive capacityVivo modelingAutoimmune encephalitisEAE severityImmunosuppressive subsetAutoimmune diseasesImmunomodulatory roleSuppressive capacityImmune cellsDisease onsetDistinct molecular classesSusceptibility lociGenetic susceptibility lociSingle-cell RNA sequencingDisease riskPatient samplesProtective variantsCardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure
Yamaguchi T, Sumida TS, Nomura S, Satoh M, Higo T, Ito M, Ko T, Fujita K, Sweet ME, Sanbe A, Yoshimi K, Manabe I, Sasaoka T, Taylor MRG, Toko H, Takimoto E, Naito AT, Komuro I. Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure. Nature Communications 2020, 11: 4364. PMID: 32868781, PMCID: PMC7459304, DOI: 10.1038/s41467-020-18128-x.Peer-Reviewed Original ResearchConceptsVentricular arrhythmiasDopamine D1 receptorsD1 receptorsChronic heart failureHeart failure patientsSustained ventricular tachycardiaNormal calcium handlingFailure patientsHeart failureModel miceVentricular tachycardiaPathophysiological roleCalcium handlingTherapeutic targetDopamine systemSingle-cell resolution analysisArrhythmiasD1RCardiomyocytesReceptorsTachycardiaPatientsMiceComplement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes
Naito AT, Sumida T, Nomura S, Liu ML, Higo T, Nakagawa A, Okada K, Sakai T, Hashimoto A, Hara Y, Shimizu I, Zhu W, Toko H, Katada A, Akazawa H, Oka T, Lee JK, Minamino T, Nagai T, Walsh K, Kikuchi A, Matsumoto M, Botto M, Shiojima I, Komuro I. Complement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes. Cell 2012, 149: 1298-1313. PMID: 22682250, PMCID: PMC3529917, DOI: 10.1016/j.cell.2012.03.047.Peer-Reviewed Original ResearchConceptsComplement C1qWnt coreceptor low-density lipoprotein receptor-related protein 6Canonical Wnt signalingLow-density lipoprotein receptor-related protein 6Serum C1q concentrationLipoprotein receptor-related protein 6Age-related phenotypesWild-type miceAge-associated impairmentWnt signalingMuscle regenerationAge-associated declineYoung miceC1q treatmentC1q concentrationsSkeletal muscle regenerationMammalian agingMiceProtein 6C1qC1s inhibitionCanonical WntMultiple tissuesFrizzled receptorsWntComplement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling
Sumida T, Naito AT, Nomura S, Nakagawa A, Higo T, Hashimoto A, Okada K, Sakai T, Ito M, Yamaguchi T, Oka T, Akazawa H, Lee JK, Minamino T, Offermanns S, Noda T, Botto M, Kobayashi Y, Morita H, Manabe I, Nagai T, Shiojima I, Komuro I. Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling. Nature Communications 2015, 6: 6241. PMID: 25716000, PMCID: PMC4351572, DOI: 10.1038/ncomms7241.Peer-Reviewed Original ResearchConceptsVascular smooth muscle cellsProliferation of VSMCsArterial remodellingΒ-catenin signalingΒ-cateninComplement C1qBlood pressure elevationEnd-organ damageNovel therapeutic targetSmooth muscle cellsMacrophage depletionImmune cellsPrecise molecular mechanismsTherapeutic targetStructural remodellingMuscle cellsRemodellingHypertensionArteriosclerosisComplement C1ActivationC1qMolecular mechanismsSignalingGene deletionRegulatory T cells in peripheral tissue tolerance and diseases
Cheru N, Hafler D, Sumida T. Regulatory T cells in peripheral tissue tolerance and diseases. Frontiers In Immunology 2023, 14: 1154575. PMID: 37197653, PMCID: PMC10183596, DOI: 10.3389/fimmu.2023.1154575.Peer-Reviewed Original ResearchConceptsTissue-resident TregsRegulatory T cellsT cellsResident TregsTissue TregsAutoimmune diseasesCommon human autoimmune diseasesAutoreactive T cellsHuman autoimmune diseasesNon-immune cellsNon-lymphoid tissuesTissue-resident cellsTreg poolTreg studiesEffector cytokinesPeripheral toleranceTreg functionIPEX syndromeImmune homeostasisSpecific tissue environmentsTregsSuppressive functionLoss of functionResident cellsGene signatureActivated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity
Sumida T, Lincoln MR, Ukeje CM, Rodriguez DM, Akazawa H, Noda T, Naito AT, Komuro I, Dominguez-Villar M, Hafler DA. Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nature Immunology 2018, 19: 1391-1402. PMID: 30374130, PMCID: PMC6240373, DOI: 10.1038/s41590-018-0236-6.Peer-Reviewed Original ResearchConceptsProstaglandin E receptor 2Regulatory T cellsTreg cellsT cellsAnti-inflammatory cytokine productionIL-10 productionPeripheral immune toleranceIL-10 expressionΒ-cateninE receptor 2Treg subpopulationsTreg phenotypeIL-10Cytokines IFNImmune toleranceTreg signatureCytokine signatureMultiple sclerosisAutoimmune diseasesCytokine productionInflammatory environmentLethal autoimmunityReceptor 2Activated β-cateninIFN
2024
An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction
Sumida T, Lincoln M, He L, Park Y, Ota M, Oguchi A, Son R, Yi A, Stillwell H, Leissa G, Fujio K, Murakawa Y, Kulminski A, Epstein C, Bernstein B, Kellis M, Hafler D. An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction. Science Translational Medicine 2024, 16: eadp1720. PMID: 39196959, DOI: 10.1126/scitranslmed.adp1720.Peer-Reviewed Original ResearchConceptsForkhead box P3Autoimmune diseasesCD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cellsMultiple sclerosisFoxp3<sup>+</sup> regulatory T cellsRegulatory T cell dysfunctionPR domain zinc finger protein 1Zinc finger protein 1Glucocorticoid-regulated kinase 1Regulatory T cellsT cell dysfunctionDisorder of young adultsAutoimmune disease multiple sclerosisDisease multiple sclerosisExpression of serumTranscriptional circuitsEpigenomic profilingShort isoformPrevent autoimmunityUpstream regulatorT cellsHuman autoimmunityEvolutionary emergenceKinase 1Molecular mechanisms
2021
Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
Rui J, Deng S, Perdigoto AL, Ponath G, Kursawe R, Lawlor N, Sumida T, Levine-Ritterman M, Stitzel ML, Pitt D, Lu J, Herold KC. Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes. Nature Communications 2021, 12: 5074. PMID: 34417463, PMCID: PMC8379260, DOI: 10.1038/s41467-021-25367-z.Peer-Reviewed Original ResearchConceptsImmune cellsΒ-cellsNOD/SCID recipientsDiabetogenic immune cellsDiabetogenic T cellsBone marrow transplantType 1 diabetesExpression of TET2Human β-cellsIslet infiltratesSCID recipientsMarrow transplantInflammatory pathwaysTransfer of diseaseT cellsInflammatory genesImmune killingPathologic interactionsReduced expressionDiabetesInflammationTET2MiceRecipientsCells
2019
Activation of DNA Damage Response and Cellular Senescence in Cardiac Fibroblasts Limit Cardiac Fibrosis After Myocardial Infarction
Shibamoto M, Higo T, Naito AT, Nakagawa A, Sumida T, Okada K, Sakai T, Kuramoto Y, Yamaguchi T, Ito M, Masumura Y, Higo S, Lee JK, Hikoso S, Komuro I, Sakata Y. Activation of DNA Damage Response and Cellular Senescence in Cardiac Fibroblasts Limit Cardiac Fibrosis After Myocardial Infarction. International Heart Journal 2019, 60: 944-957. PMID: 31257341, DOI: 10.1536/ihj.18-701.Peer-Reviewed Original ResearchConceptsCellular senescenceDNA damage response systemDNA damage responseCardiac fibroblastsDDR activationDamage responseMolecular mechanismsSenescenceGene deletionJuxtacrine mannerProliferation of CFsCardiac fibrosisCF proliferationProliferationCardiac remodelingActivationTissue fibrosisRemodelingImportant roleTherapeutic strategiesRoleRecent reportsDeletionRegulationATM gene deletionAedes aegypti AgBR1 antibodies modulate early Zika virus infection of mice
Uraki R, Hastings AK, Marin-Lopez A, Sumida T, Takahashi T, Grover JR, Iwasaki A, Hafler DA, Montgomery RR, Fikrig E. Aedes aegypti AgBR1 antibodies modulate early Zika virus infection of mice. Nature Microbiology 2019, 4: 948-955. PMID: 30858571, PMCID: PMC6533137, DOI: 10.1038/s41564-019-0385-x.Peer-Reviewed Original ResearchConceptsZika virus infectionVirus infectionZika virusAegypti salivary proteinsGuillain-Barre syndromeEarly inflammatory responseSkin of micePrevention of mosquitoInflammatory responseAedes aegypti mosquitoesTherapeutic measuresSalivary factorsSalivary proteinsMosquito-borneInfectionMiceSubstantial mortalityRecent epidemicProtein 1Aegypti mosquitoesAntigenic proteinsVirusAntibodiesMosquitoesAntiserumHigh-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload
Satoh M, Nomura S, Harada M, Yamaguchi T, Ko T, Sumida T, Toko H, Naito AT, Takeda N, Tobita T, Fujita T, Ito M, Fujita K, Ishizuka M, Kariya T, Akazawa H, Kobayashi Y, Morita H, Takimoto E, Aburatani H, Komuro I. High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload. Journal Of Molecular And Cellular Cardiology 2019, 128: 77-89. PMID: 30611794, DOI: 10.1016/j.yjmcc.2018.12.018.Peer-Reviewed Original ResearchConceptsTransverse aortic constrictionHemodynamic overloadCardiomyocyte sizeExpression levelsGene expressionHeart failure stageSingle-cell RNA sequencingSingle-molecule RNAMyosin heavy chain βSingle-cell quantitative PCRFetal gene expressionFetal gene programSingle-cell analysis methodsSingle-molecule fluorescenceHeart failureSingle-cell levelPressure overloadAortic constrictionHypertrophy stageCardiac hypertrophyIsolated cardiomyocytesMyh7 expressionTemporal regulationRNA sequencingFetal genes
2018
Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure
Nomura S, Satoh M, Fujita T, Higo T, Sumida T, Ko T, Yamaguchi T, Tobita T, Naito AT, Ito M, Fujita K, Harada M, Toko H, Kobayashi Y, Ito K, Takimoto E, Akazawa H, Morita H, Aburatani H, Komuro I. Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure. Nature Communications 2018, 9: 4435. PMID: 30375404, PMCID: PMC6207673, DOI: 10.1038/s41467-018-06639-7.Peer-Reviewed Original ResearchConceptsCardiac hypertrophyCardiomyocyte remodelingGene programHeart failurePressure overloadMorphological hypertrophyHeart functionHypertrophyP53 deletionEarly hypertrophyFunctional signaturesFunctional phenotypeLate hypertrophyP53 signalingTranscriptional signatureProgram activationMitochondrial inhibitionUnderlying mechanismCardiomyocyte identityCardiomyocytesMitochondrial activationRemodelingFailureTranscriptional programsActivation
2017
DNA single-strand break-induced DNA damage response causes heart failure
Higo T, Naito AT, Sumida T, Shibamoto M, Okada K, Nomura S, Nakagawa A, Yamaguchi T, Sakai T, Hashimoto A, Kuramoto Y, Ito M, Hikoso S, Akazawa H, Lee JK, Shiojima I, McKinnon PJ, Sakata Y, Komuro I. DNA single-strand break-induced DNA damage response causes heart failure. Nature Communications 2017, 8: 15104. PMID: 28436431, PMCID: PMC5413978, DOI: 10.1038/ncomms15104.Peer-Reviewed Original ResearchConceptsPressure overload-induced heart failureOverload-induced heart failureHeart failureSingle-strand breaksNF-κB signalingNew therapeutic strategiesSSB accumulationDDR activationInflammatory cytokinesTherapeutic strategiesUnrepaired single-strand breaksDNA damageDNA single-strand breaksCausative roleDNA damage responseGenetic deletionPathogenesisActivationPivotal roleFailureDamage responseHeartCritical roleCytokinesMice
2016
Activation of endothelial β-catenin signaling induces heart failure
Nakagawa A, Naito AT, Sumida T, Nomura S, Shibamoto M, Higo T, Okada K, Sakai T, Hashimoto A, Kuramoto Y, Oka T, Lee JK, Harada M, Ueda K, Shiojima I, Limbourg FP, Adams RH, Noda T, Sakata Y, Akazawa H, Komuro I. Activation of endothelial β-catenin signaling induces heart failure. Scientific Reports 2016, 6: 25009. PMID: 27146149, PMCID: PMC4857119, DOI: 10.1038/srep25009.Peer-Reviewed Original ResearchConceptsWnt/β-cateninHeart failureCardiac dysfunctionCa miceEndothelial cellsΒ-cateninEndothelial β-cateninProgressive cardiac dysfunctionCardiac endothelial cellsDegeneration of mitochondriaArterial endothelial cellsNeuregulin-ErbB signalingNeuregulin proteinΒ-catenin-dependent canonical WntEndothelial expressionIschemic diseasesTherapeutic targetDysfunctionMiceSustained activationFunction mutationsNeuregulin-ErbBT-tubulesCanonical WntConditional gain
2015
Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression
Yabumoto C, Akazawa H, Yamamoto R, Yano M, Kudo-Sakamoto Y, Sumida T, Kamo T, Yagi H, Shimizu Y, Saga-Kamo A, Naito AT, Oka T, Lee JK, Suzuki J, Sakata Y, Uejima E, Komuro I. Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression. Scientific Reports 2015, 5: 14453. PMID: 26571361, PMCID: PMC4585890, DOI: 10.1038/srep14453.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, TopicalAgingAngiotensin II Type 1 Receptor BlockersAnimalsAxin ProteinBiphenyl CompoundsCell LineComplement C1qDown-RegulationImmunohistochemistryIrbesartanMacrophagesMaleMiceMice, Inbred C57BLMice, KnockoutMuscle, SkeletalPAX7 Transcription FactorReceptor, Angiotensin, Type 1RegenerationTetrazolesWnt Signaling PathwayConceptsC1q expressionReceptor blockadeAge-related declineAngiotensin II receptor blockadeAT1 receptor blocker irbesartanAngiotensin II type 1 receptorII type 1 receptorAT1 receptor blockadeFunctional muscle recoveryII receptor blockadeSkeletal muscleReceptor blocker irbesartanType 1 receptorWnt/β-catenin pathwaySkeletal muscle functionWnt/β-catenin signalingMuscle regenerationΒ-catenin pathwayCultured macrophage cellsΒ-catenin signalingAT1 receptorMuscle recoveryM2 polarizationMuscle functionTopical administrationA Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling
Nakayama A, Morita H, Nakao T, Yamaguchi T, Sumida T, Ikeda Y, Kumagai H, Motozawa Y, Takahashi T, Imaizumi A, Hashimoto T, Nagai R, Komuro I. A Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling. PLOS ONE 2015, 10: e0137106. PMID: 26327560, PMCID: PMC4556625, DOI: 10.1371/journal.pone.0137106.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin IIAnimalsAntioxidantsAtrial Natriuretic FactorConnective Tissue Growth FactorDietFibroblastsFibrosisFlavonoidsFoodHeartHydrogen PeroxideHypertrophyLuteolinMaleMyocardiumOxidative StressPhosphorylationRatsRats, Sprague-DawleySignal TransductionTransforming Growth Factor beta1Ventricular RemodelingConceptsCardiac remodelingAng IIOral pretreatmentII-Induced Cardiac RemodelingOxidative stressCultured rat cardiac fibroblastsRat cardiac fibroblastsPhosphorylation of JNKHyperoxidative stateAntifibrotic effectsCardiac fibrosisCardiac functionLuteolin pretreatmentTGFβ1 expressionCardiac fibroblastsPotent antioxidantHerbal extractsProtective actionCardiac tissueRemodelingExpression levelsGene expression levelsDietPretreatmentProtective propertiesWnt/&bgr;-Catenin Signaling Contributes to Skeletal Myopathy in Heart Failure via Direct Interaction With Forkhead Box O
Okada K, Naito AT, Higo T, Nakagawa A, Shibamoto M, Sakai T, Hashimoto A, Kuramoto Y, Sumida T, Nomura S, Ito M, Yamaguchi T, Oka T, Akazawa H, Lee JK, Morimoto S, Sakata Y, Shiojima I, Komuro I. Wnt/&bgr;-Catenin Signaling Contributes to Skeletal Myopathy in Heart Failure via Direct Interaction With Forkhead Box O. Circulation Heart Failure 2015, 8: 799-808. PMID: 26038536, DOI: 10.1161/circheartfailure.114.001958.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBeta CateninCardiomyopathy, DilatedCell LineComplement C1qDisease Models, AnimalForkhead Box Protein O1Forkhead Transcription FactorsMice, TransgenicMuscle FatigueMuscle Fibers, SkeletalMuscle, SkeletalMuscular DiseasesRNA InterferenceTransfectionWnt Signaling PathwayWnt3A ProteinConceptsChronic heart failureFiber type shiftFatigable fibersSkeletal myopathyActivation of WntHeart failureModel miceCardiomyopathy miceSkeletal muscleNovel therapeutic targetMediator β-cateninType IIB fibersControl miceType shiftC2C12 cellsTherapeutic targetSignaling contributesComplement C1qMyopathyMiceCritical roleIIB fibersForkhead box OΒ-cateninFoxO1 activity
2010
Promotion of CHIP-Mediated p53 Degradation Protects the Heart From Ischemic Injury
Naito AT, Okada S, Minamino T, Iwanaga K, Liu ML, Sumida T, Nomura S, Sahara N, Mizoroki T, Takashima A, Akazawa H, Nagai T, Shiojima I, Komuro I. Promotion of CHIP-Mediated p53 Degradation Protects the Heart From Ischemic Injury. Circulation Research 2010, 106: 1692-1702. PMID: 20413784, DOI: 10.1161/circresaha.109.214346.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornApoptosisBase SequenceBenzoquinonesCell HypoxiaChlorocebus aethiopsCOS CellsDisease Models, AnimalGenetic TherapyHSP90 Heat-Shock ProteinsHumansHypoxia-Inducible Factor 1, alpha SubunitLactams, MacrocyclicMaleMiceMice, Inbred C57BLMice, KnockoutMolecular Sequence DataMutationMyocardial InfarctionMyocytes, CardiacPromoter Regions, GeneticProteasome Endopeptidase ComplexProtein Processing, Post-TranslationalRatsRats, WistarRNA InterferenceTranscriptional ActivationTumor Suppressor Protein p53Ubiquitin-Protein LigasesUbiquitinationVentricular RemodelingConceptsMyocardial infarctionP53 accumulationCardiomyocyte apoptosisCoronary heart diseaseNumber of patientsNovel therapeutic strategiesP53 degradationApoptosis of cardiomyocytesHeat shock proteinsHeart failureIschemic injuryCardioprotective effectsVentricular remodelingCHIP overexpressionHeart diseaseInfarctionTherapeutic strategiesProteasomal degradationMyocardial apoptosisAmount of p53Molecular mechanismsShock proteinsP53 antagonistP53 accumulatesProtein levels