2020
Profibrotic Activation of Human Macrophages in Systemic Sclerosis
Bhandari R, Ball MS, Martyanov V, Popovich D, Schaafsma E, Han S, ElTanbouly M, Orzechowski NM, Carns M, Arroyo E, Aren K, Hinchcliff M, Whitfield ML, Pioli PA. Profibrotic Activation of Human Macrophages in Systemic Sclerosis. Arthritis & Rheumatology 2020, 72: 1160-1169. PMID: 32134204, PMCID: PMC7329566, DOI: 10.1002/art.41243.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntigens, CDAntigens, Differentiation, MyelomonocyticCell DifferentiationChemokine CCL2Coculture TechniquesFemaleFibroblastsFibrosisHLA-DR AntigensHumansImmunophenotypingInterleukin-6Lectins, C-TypeLeukocytes, MononuclearMacrophage ActivationMacrophagesMaleMannose ReceptorMannose-Binding LectinsMiddle AgedMonocytesPhosphorylationReceptor, Transforming Growth Factor-beta Type IReceptor, Transforming Growth Factor-beta Type IIReceptors, Cell SurfaceRNA, MessengerScleroderma, SystemicSkinSTAT3 Transcription FactorTranscriptomeTransforming Growth Factor betaConceptsPeripheral blood mononuclear cellsSystemic sclerosisSSc patientsBasal conditionsSex-matched healthy controlsSSc fibroblastsSurface markersHealthy donor monocytesBlood mononuclear cellsMediator of fibrosisInflammatory macrophage activationMonocyte-derived macrophagesActivation profilesGrowth factor βFibrotic activationGene expression signaturesDonor monocytesMononuclear cellsProfibrotic activationSkin fibrosisInterleukin-6Healthy controlsSSc skinIndependent cohortMacrophage activation
2015
The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling
Wei J, Ghosh AK, Chu H, Fang F, Hinchcliff ME, Wang J, Marangoni RG, Varga J. The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling. Arthritis & Rheumatology 2015, 67: 1323-1334. PMID: 25707573, PMCID: PMC4518870, DOI: 10.1002/art.39061.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCase-Control StudiesCells, CulturedDisease Models, AnimalEnzyme InhibitorsFibroblastsHumansMiceP300-CBP Transcription FactorsPlatelet-Derived Growth FactorReal-Time Polymerase Chain ReactionResveratrolRNA, MessengerScleroderma, SystemicSignal TransductionSirtuin 1SkinSmad ProteinsStilbenesTransforming Growth Factor betaConceptsGenome-wide expression data setsTransforming Growth Factor β SignalingGrowth factor β signalingSSc skin biopsy samplesSirtuin 1Histone deacetylase sirtuin 1Tissue expressionExpression data setsPlatelet-derived growth factorTranscriptome dataDeacetylase sirtuin 1Epigenetic mechanismsAcetyltransferase p300Acetylation statusEnzyme sirtuin 1Persistent fibroblast activationEffect of SIRT1Β signalingMessenger RNA levelsMouse fibroblastsFibrotic responseLoss of SIRT1Activation of SIRT1Pharmacologic inhibitionExperimental fibrosis model
2014
FibronectinEDA Promotes Chronic Cutaneous Fibrosis Through Toll-Like Receptor Signaling
Bhattacharyya S, Tamaki Z, Wang W, Hinchcliff M, Hoover P, Getsios S, White ES, Varga J. FibronectinEDA Promotes Chronic Cutaneous Fibrosis Through Toll-Like Receptor Signaling. Science Translational Medicine 2014, 6: 232ra50. PMID: 24739758, PMCID: PMC4414050, DOI: 10.1126/scitranslmed.3008264.Peer-Reviewed Original ResearchConceptsToll-like receptor 4Endogenous TLR4 ligandsCutaneous fibrosisTLR4 ligandToll-like receptor signalingProgressive autoimmune diseaseLesional skin biopsiesFibronectin extra domain ATreatment of fibrosisTissue repair responseHallmark of sclerodermaPersistent fibroblast activationExtra domain ATLR4 blockadeAutoimmune diseasesChronic conditionsChronic fibrosisReceptor 4Skin biopsiesFibrotic responseOrganotypic skin equivalentsMultiple organsPotent stimulusSclerodermaFibroblast activation
2013
Early Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-β and Regulates Fibrogenic Responses
Fang F, Shangguan AJ, Kelly K, Wei J, Gruner K, Ye B, Wang W, Bhattacharyya S, Hinchcliff ME, Tourtellotte WG, Varga J. Early Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-β and Regulates Fibrogenic Responses. American Journal Of Pathology 2013, 183: 1197-1208. PMID: 23906810, PMCID: PMC3791870, DOI: 10.1016/j.ajpath.2013.06.016.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsDisease Models, AnimalEarly Growth Response Protein 1Early Growth Response Protein 2Early Growth Response Protein 3FemaleFibroblastsFibrosisGene Expression ProfilingGene Expression RegulationHumansIntracellular SpaceMaleMiceMice, Inbred BALB CMiddle AgedScleroderma, SystemicSignal TransductionSkinSmad ProteinsTransforming Growth Factor betaConceptsEgr-3Genome-wide expression profilingSubstantial functional divergenceEarly growth response (EGR) gene familyEarly growth response 3Egr family membersFunctional divergenceGene familyFibroblast genesGrowth factorTranscription factorsExpression profilingBiological functionsGene expressionDistinct membersEgr familyEgr-1Canonical Smad3Distinct rolesEgr-2Normal skin fibroblastsTissue remodelingFibrotic gene expressionGenesFirst evidenceA synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses
Wei J, Zhu H, Komura K, Lord G, Tomcik M, Wang W, Doniparthi S, Tamaki Z, Hinchcliff M, Distler JH, Varga J. A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses. Annals Of The Rheumatic Diseases 2013, 73: 446. PMID: 23515440, PMCID: PMC4028127, DOI: 10.1136/annrheumdis-2012-202716.Peer-Reviewed Original ResearchMeSH KeywordsAdipogenesisAdultAnimalsBiopsyCells, CulturedCollagenDisease Models, AnimalDrug Evaluation, PreclinicalFemaleFibroblastsFibrosisHumansInfant, NewbornMiceMice, Inbred C57BLOleanolic AcidOrgan Culture TechniquesPPAR gammaProto-Oncogene Proteins c-aktScleroderma, SystemicSignal TransductionSkinTransforming Growth Factor betaConceptsSkin organ cultureHuman skin organ cultureAntifibrotic effectsDermal fibrosisExperimental fibrosisOrgan culturePeroxisome proliferator-activated receptor γModulation of fibrogenesisProliferator-activated receptor γHuman skin equivalentsPotential new therapiesPotential therapeutic strategyFibrotic gene expressionSynthetic oleanane triterpenoidComplementary mouse modelsControl of fibrosisPersistent fibroblast activationGrowth factor βTGF-β signalingEffects of CDDOSystemic sclerosisBleomycin injectionFibrogenic responseFibrotic activityMurine model
2009
A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate
Bhattacharyya S, Ishida W, Wu M, Wilkes M, Mori Y, Hinchcliff M, Leof E, Varga J. A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate. Oncogene 2009, 28: 1285-1297. PMID: 19151753, PMCID: PMC4006376, DOI: 10.1038/onc.2008.479.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBleomycinCells, CulturedCollagenEarly Growth Response Protein 1Extracellular Signal-Regulated MAP KinasesFibroblastsFibrosisHumansImatinib MesylateMiceMice, Inbred BALB CNIH 3T3 CellsPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-ablPyrimidinesSignal TransductionSmad2 ProteinSmad3 ProteinTransforming Growth Factor betaConceptsChronic myelogenous leukemiaFibrotic responseEgr-1Growth factorUpregulated tissue expressionFibrosis of skinNovel therapeutic approachesEarly growth response factor-1Kinase-deficient mutant formC-AblNormal fibroblastsTGF-β stimulationIntracellular signaling mechanismLesional skinStimulation of collagenImatinib mesylateMouse embryonic fibroblastsFibrotic processMyelogenous leukemiaTherapeutic approachesPharmacological targetingTarget of inhibitionTGF-β responseFibroblast activationC-Abl activation
2007
Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-β responsiveness
Mori Y, Hinchcliff M, Wu M, Warner-Blankenship M, Lyons K, Varga J. Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-β responsiveness. Experimental Cell Research 2007, 314: 1094-1104. PMID: 18201696, PMCID: PMC3963386, DOI: 10.1016/j.yexcr.2007.12.010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell ProliferationCells, CulturedCollagenCollagen Type IConnective Tissue Growth FactorEmbryo, MammalianExtracellular MatrixFibroblastsFibrosisGene ExpressionImmediate-Early ProteinsIntercellular Signaling Peptides and ProteinsMiceSignal TransductionSmad ProteinsTransforming Growth Factor betaConceptsEmbryonic fibroblastsSmad-dependent transcriptional responsesTGF-beta signal transductionMatricellular protein connective tissue growth factorMurine embryonic fibroblastsMouse embryonic fibroblastsProtein connective tissue growth factorWild-type MEFsTransient transfection assaysMyofibroblast transdifferentiationCCN2 expressionRegulation of proliferationCorresponding protein levelsCCN2 functionsCollagen gene expressionTranscriptional responseRT-PCR analysisLoss of CCN2Signal transductionEndogenous CCN2Transfection assaysExtracellular matrix synthesisMouse embryosGene expressionWild type