Featured Publications
MIF is a common genetic determinant of COVID-19 symptomatic infection and severity
Shin JJ, Fan W, Par-Young J, Piecychna M, Leng L, Israni-Winger K, Qing H, Gu J, Zhao H, Schulz WL, Unlu S, Kuster J, Young G, Liu J, Ko AI, Garcia A, Sauler M, Wisnewski AV, Young L, Orduña A, Wang A, Klementina O, Garcia AB, Hegyi P, Armstrong ME, Mitchell P, Ordiz DB, Garami A, Kang I, Bucala R. MIF is a common genetic determinant of COVID-19 symptomatic infection and severity. QJM 2022, 116: 205-212. PMID: 36222594, PMCID: PMC9620729, DOI: 10.1093/qjmed/hcac234.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorLow-expression MIF alleleCOVID-19 infectionMIF allelesCATT7 alleleHealthy controlsCOVID-19Serum macrophage migration inhibitory factorSymptomatic SARS-CoV-2 infectionHigh-expression MIF allelesHigher serum MIF levelsRetrospective case-control studySARS-CoV-2 infectionFunctional polymorphismsAvailable clinical characteristicsMultinational retrospective studySerum MIF levelsUninfected healthy controlsSymptomatic COVID-19Tertiary medical centerHealthy control subjectsCase-control studyMigration inhibitory factorCoronavirus disease 2019Common functional polymorphisms
2024
Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia
Huang Y, Chen L, Li L, Qi Y, Tong H, Wu H, Xu J, Leng L, Cheema S, Sun G, Xia Z, McGuire J, Rodrigues B, Young L, Bucala R, Qi D. Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia. JCI Insight 2024, 9: e173240. PMID: 38973609, PMCID: PMC11383372, DOI: 10.1172/jci.insight.173240.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorDevelopment of hypertriglyceridemiaWhite adipose tissueAdipose LPLPAR2 expressionLevels of macrophage migration inhibitory factorElevated plasma TG levelsLPL expressionLipoprotein lipaseIncrease PAR2 expressionPlasma MIF levelsPlasma TG levelsMigration inhibitory factorPalmitic acid dietInhibited Akt phosphorylationMIF levelsLipoprotein lipase geneTG levelsObese humansPlasma TGHypertriglyceridemiaAkt phosphorylationLipid storageInhibitory factorAdipose tissueMIF-Modulated Spinal Proteins Associated with Persistent Bladder Pain: A Proteomics Study
Ye S, Agalave N, Ma F, Mahmood D, Al-Grety A, Khoonsari P, Leng L, Svensson C, Bucala R, Kultima K, Vera P. MIF-Modulated Spinal Proteins Associated with Persistent Bladder Pain: A Proteomics Study. International Journal Of Molecular Sciences 2024, 25: 4484. PMID: 38674069, PMCID: PMC11050327, DOI: 10.3390/ijms25084484.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, Differentiation, B-LymphocyteCystitis, InterstitialDisease Models, AnimalFemaleHistocompatibility Antigens Class IIHyperalgesiaIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMiceProteomicsReceptors, CXCR4Receptors, ImmunologicSpinal CordUrinary BladderConceptsMacrophage migration inhibitory factorProtease activated receptor 4C-X-C chemokine receptor type 4Bladder hyperalgesiaBladder painSpinal proteinsMIF receptor CD74MIF antagonismL6-S1 spinal segmentsSpinal mechanismsInterstitial cystitis/bladder pain syndromeMIF receptorSeparate groups of miceChemokine receptor type 4Associated with reliefGroups of miceC-X-CMigration inhibitory factorChanges compared to controlsBladder inflammationPain syndromeFemale miceNo significant changesSham i.Receptor 4IL-1 receptor 1 signaling shapes the development of viral antigen-specific CD4+ T cell responses following COVID-19 mRNA vaccination
Park H, Shin M, Shin J, Kim H, Kang B, Par-Young J, Unlu S, Afinogenova Y, Catanzaro J, Young J, Kim M, Lee S, Jeon S, You S, Racke M, Bucala R, Kang I. IL-1 receptor 1 signaling shapes the development of viral antigen-specific CD4+ T cell responses following COVID-19 mRNA vaccination. EBioMedicine 2024, 103: 105114. PMID: 38640835, PMCID: PMC11041015, DOI: 10.1016/j.ebiom.2024.105114.Peer-Reviewed Original ResearchConceptsCD4<sup>+</sup> T cellsCOVID-19 mRNA vaccinesAntigen-specific CD4<sup>+</sup> T cell responsesT cell responsesPrimary antibody deficiencyCD4<sup>+</sup> T cell responsesT cellsIL-1R1MRNA vaccinesIL-1IgG antibodiesAntigen-specific CD4<sup>+</sup> T cellsCD4+ T cell responsesLevels of IL-1R1Human CD4<sup>+</sup> T cellsIL-1 receptor 1Healthy individualsDose of COVID-19 mRNA vaccineAntigen-specific CD4IL-1R1 expressionT cell immunityRepetitive antigenic stimulationCytokines interleukin (IL)-1Immune response to virusesExpression of IL-1R1
2023
Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) are significant promotors of UVB- but not chemically induced non-melanoma skin cancer
Huth S, Huth L, Heise R, Marquardt Y, Lopopolo L, Piecychna M, Boor P, Fingerle-Rowson G, Kapurniotu A, Yazdi A, Bucala R, Bernhagen J, Baron J. Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) are significant promotors of UVB- but not chemically induced non-melanoma skin cancer. Scientific Reports 2023, 13: 11611. PMID: 37464010, PMCID: PMC10354066, DOI: 10.1038/s41598-023-38748-9.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorNon-melanoma skin cancerD-DTSkin cancerRecombinant macrophage migration inhibitory factorUVB irradiationAcute UVB irradiationPrevention of photocarcinogenesisMigration inhibitory factorAccumulation of macrophagesAdditive protective effectChronic UVB irradiationDouble knockout micePotential therapeutic targetMacrophage accumulationCommon cancerPathophysiological roleProtective effectSkin tumorsKnockout miceTherapeutic targetInhibitory factorGenetic deletionCytokinesCancerUrothelial Oxidative Stress and ERK Activation Mediate HMGB1-Induced Bladder Pain
Ye S, Mahmood D, Ma F, Leng L, Bucala R, Vera P. Urothelial Oxidative Stress and ERK Activation Mediate HMGB1-Induced Bladder Pain. Cells 2023, 12: 1440. PMID: 37408274, PMCID: PMC10217556, DOI: 10.3390/cells12101440.Peer-Reviewed Original ResearchConceptsHigh mobility group box 1Macrophage migration inhibitory factorBladder painOxidative stressDisulfide HMGB1Mobility group box 1MIF-deficient miceNovel potential therapeutic strategyMigration inhibitory factorGroup box 1Potential therapeutic strategyOxidative stress productionN-acetylcysteine amideERK activationIntravesical treatmentMicturition volumeMicturition parametersReceptor 4Mechanical thresholdPainTherapeutic strategiesBox 1Bladder tissueInhibitory factorWestern blot
2022
“Near Cure” treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct
Vandenbark AA, Meza-Romero R, Wiedrick J, Gerstner G, Seifert H, Kent G, Piechycna M, Benedek G, Bucala R, Offner H. “Near Cure” treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct. Cellular Immunology 2022, 378: 104561. PMID: 35738135, PMCID: PMC9714992, DOI: 10.1016/j.cellimm.2022.104561.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisAcute experimental autoimmune encephalomyelitisDRα1-MOG-35Multiple sclerosisMIF-1EAE scoresMale miceMIF-2Severe diseaseMacrophage migration inhibitory factorClinical EAE scoresMIF-deficient micePeripheral inflammatory cellsMigration inhibitory factorSpinal cord tissueT cell activationSex-dependent differencesEAE severityAutoimmune encephalomyelitisSerum levelsTreatment of WTInflammatory cellsFemale miceClinical signsCord tissueInterleukin-17 Contributes to Chikungunya Virus-Induced Disease
Liu X, Poo YS, Alves JC, Almeida RP, Mostafavi H, Tang PCH, Bucala R, Teixeira MM, Taylor A, Zaid A, Mahalingam S. Interleukin-17 Contributes to Chikungunya Virus-Induced Disease. MBio 2022, 13: e00289-22. PMID: 35254128, PMCID: PMC9040832, DOI: 10.1128/mbio.00289-22.Peer-Reviewed Original ResearchConceptsIL-17Chikungunya virusCHIKV infectionRheumatoid arthritisIL-17-deficient miceIL-17A-deficient miceInterleukin-17 ContributesSpecific antiviral drugsWild-type miceIL-17 signalingAlphaviral arthritidesIL-17AIL-23Neutrophil infiltrationPsoriatic arthritisArthritic inflammationIL-21Acute phaseIL-22Interleukin-17Chronic phaseIL-6Tissue infiltratesTissue inflammationDisease patientsMacrophage migration inhibitory factor regulates specific innate immune sensor responses in gingival epithelial cells
Kantrong N, Chang AM, Bamashmous S, Hajjar AM, Bucala RJ, Darveau RP. Macrophage migration inhibitory factor regulates specific innate immune sensor responses in gingival epithelial cells. Journal Of Periodontology 2022, 93: 1940-1950. PMID: 35100435, DOI: 10.1002/jper.21-0598.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorGingival epithelial cellsIL-8/CXCL8Migration inhibitory factorGingival tissuesJunctional epitheliumGingival epitheliumRole of MIFInhibitory factorMIF KO miceEpithelial cellsExpression of TLR4Healthy gingival tissuesToll-like receptorsInterleukin-1 receptorRepertoire of receptorsOral healthNeutrophil chemoattractantIL-1R1IL-1R2Neutrophil regulationKO micePeriodontal tissuesIL-1ROral homeostasis
2021
MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model
Tilstam PV, Schulte W, Holowka T, Kim BS, Nouws J, Sauler M, Piecychna M, Pantouris G, Lolis E, Leng L, Bernhagen J, Fingerle-Rowson G, Bucala R. MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model. Journal Of Clinical Investigation 2021, 131: e127171. PMID: 34850744, PMCID: PMC8631602, DOI: 10.1172/jci127171.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCytokinesDisease Models, AnimalFemaleFlow CytometryGene Expression ProfilingInflammationIntramolecular OxidoreductasesLeukocyte CountMacrophage Migration-Inhibitory FactorsMacrophagesMacrophages, PeritonealMaleMiceMice, Inbred C57BLMice, TransgenicPeritoneal LavagePhenotypeProtein BindingRNA-SeqSepsisSignal TransductionConceptsMacrophage migration inhibitory factorSmall peritoneal macrophagesLarge peritoneal macrophagesPolymicrobial sepsisPeritoneal macrophagesMIF receptor CD74MIF promoter polymorphismsMIF-2Migration inhibitory factorPolymicrobial sepsis modelMIF deficiencyAdoptive transferSeptic shockSurvival benefitInfectious insultsMIF antibodyExcessive inflammationInflammatory cytokinesReceptor CD74Sepsis modelProtective effectPeritoneal cavityDifferent infectionsPromoter polymorphismInflammatory macrophagesMacrophage migration inhibitory factor exerts pro‐proliferative and anti‐apoptotic effects via CD74 in murine hepatocellular carcinoma
Wirtz TH, Saal A, Bergmann I, Fischer P, Heinrichs D, Brandt EF, Koenen MT, Djudjaj S, Schneider KM, Boor P, Bucala R, Weiskirchen R, Bernhagen J, Trautwein C, Berres M. Macrophage migration inhibitory factor exerts pro‐proliferative and anti‐apoptotic effects via CD74 in murine hepatocellular carcinoma. British Journal Of Pharmacology 2021, 178: 4452-4467. PMID: 34250589, DOI: 10.1111/bph.15622.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorMIF/CD74 axisMigration inhibitory factorHepatocellular carcinomaRole of MIFInhibitory factorReduced tumor burdenAnti-CD74 antibodiesNew pharmacological therapiesDEN/CClDifferent inflammatory diseasesChemokine-like proteinTherapy-induced cell deathMurine hepatocellular carcinomaPro-tumorigenic roleAnti-apoptotic effectsCarbon tetrachloride modelTherapy-induced apoptosisMIF knockoutMIF receptorPharmacological therapyTumor burdenControl miceReceptor CD74CD74 antibodyIntravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain
Ye S, Ma F, Mahmood DFD, Meyer-Siegler KL, Menard RE, Hunt DE, Leng L, Bucala R, Vera PL. Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain. PLOS ONE 2021, 16: e0255975. PMID: 34424927, PMCID: PMC8382170, DOI: 10.1371/journal.pone.0255975.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorHigh mobility group box 1Bladder painMIF receptorHMGB1 releaseBladder hyperalgesiaMobility group box 1MIF receptor CD74Migration inhibitory factorGroup box 1Primary urothelial cellsInhibitory factor receptorWarrants further investigationCD74 receptorReceptor CD74Micturition parametersReceptor antagonistReceptor 4Box 1PainInhibitory factorHyperalgesiaCD74Urothelial cellsNovel targetRole of MIF in coordinated expression of hepatic chemokines in patients with alcohol-associated hepatitis
Poulsen KL, Fan X, Kibler CD, Huang E, Wu X, McMullen MR, Leng L, Bucala R, Ventura-Cots M, Argemi J, Bataller R, Nagy LE. Role of MIF in coordinated expression of hepatic chemokines in patients with alcohol-associated hepatitis. JCI Insight 2021, 6: e141420. PMID: 33945507, PMCID: PMC8262327, DOI: 10.1172/jci.insight.141420.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorAlcohol-associated hepatitisChemokine expressionHealthy controlsLiver diseaseRole of MIFMIF KO miceChronic liver diseaseCytokines/chemokinesMigration inhibitory factorUpstream regulatorChemokine signatureChemokine CCL20WT miceCultured hepatocytesMultiple chemokinesChemokine systemInflammatory responseChemokine membersNovel therapiesEthanol feedingPatientsChemokine familyChemokinesInhibitory factor17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex
Harrison DE, Strong R, Reifsnyder P, Kumar N, Fernandez E, Flurkey K, Javors MA, Lopez‐Cruzan M, Macchiarini F, Nelson JF, Markewych A, Bitto A, Sindler AL, Cortopassi G, Kavanagh K, Leng L, Bucala R, Rosenthal N, Salmon A, Stearns TM, Bogue M, Miller RA. 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell 2021, 20: e13328. PMID: 33788371, PMCID: PMC8135004, DOI: 10.1111/acel.13328.Peer-Reviewed Original ResearchCD74 is a regulator of hematopoietic stem cell maintenance
Becker-Herman S, Rozenberg M, Hillel-Karniel C, Gil-Yarom N, Kramer M, Barak A, Sever L, David K, Radomir L, Lewinsky H, Levi M, Friedlander G, Bucala R, Peled A, Shachar I. CD74 is a regulator of hematopoietic stem cell maintenance. PLOS Biology 2021, 19: e3001121. PMID: 33661886, PMCID: PMC7963458, DOI: 10.1371/journal.pbio.3001121.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAntigens, Differentiation, B-LymphocyteBone Marrow CellsBone Marrow TransplantationCell LineageFemaleHealthy VolunteersHematopoietic Stem CellsHistocompatibility Antigens Class IIHumansIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMaleMiceMice, Inbred C57BLSignal TransductionConceptsMacrophage migration inhibitory factorHematopoietic stem cellsBone marrowCytokine macrophage migration inhibitory factorMigration inhibitory factorNumber of HSPCsTransplant protocolsCD18 expressionClinical transplantationInduced SurvivalCD74Inhibitory factorBM nicheCell surface receptorsSelf-renewal propertiesClinical insightsProgenitor cellsBlood cell lineagesSurface receptorsStem cellsHematopoietic stemCell lineagesCellsUndifferentiated cellsHematopoietic stem cell maintenance
2020
Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting
Kontos C, El Bounkari O, Krammer C, Sinitski D, Hille K, Zan C, Yan G, Wang S, Gao Y, Brandhofer M, Megens RTA, Hoffmann A, Pauli J, Asare Y, Gerra S, Bourilhon P, Leng L, Eckstein HH, Kempf WE, Pelisek J, Gokce O, Maegdefessel L, Bucala R, Dichgans M, Weber C, Kapurniotu A, Bernhagen J. Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting. Nature Communications 2020, 11: 5981. PMID: 33239628, PMCID: PMC7689490, DOI: 10.1038/s41467-020-19764-z.Peer-Reviewed Original ResearchMeSH KeywordsAgedAnimalsAntigens, CDAtherosclerosisBinding SitesCarotid Artery, CommonChemokine CXCL12Crystallography, X-RayDisease Models, AnimalDrug DesignDrug Evaluation, PreclinicalEndarterectomy, CarotidFemaleHumansIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMaleMiceMice, Knockout, ApoEMiddle AgedPeptide FragmentsReceptors, CXCR4SialyltransferasesSignal TransductionConceptsMacrophage migration inhibitory factorCXC motif chemokine receptor 4Chemokine receptorsChemokine/receptor axisCXCR4/CXCL12 interactionHuman carotid endarterectomy specimensMigration inhibitory factorChemokine receptor 4MIF/CD74Carotid endarterectomy specimensAtherogenic inflammationCXCL12 interactionReceptor axisReceptor 4MIF inhibitorsReceptor-based strategiesAtherosclerotic plaquesAtherosclerosisAtypical chemokineLeukocyte adhesionCell activityProtective pathwaysInflammationChemokinesPlaques
2001
Lysozyme Enhances Renal Excretion of Advanced Glycation Endproducts In Vivo and Suppresses Adverse AGE-mediated Cellular Effects In Vitro: A Potential AGE Sequestration Therapy for Diabetic Nephropathy?
Zheng F, Cai W, Mitsuhashi T, Vlassara H, Bucala R. Lysozyme Enhances Renal Excretion of Advanced Glycation Endproducts In Vivo and Suppresses Adverse AGE-mediated Cellular Effects In Vitro: A Potential AGE Sequestration Therapy for Diabetic Nephropathy? Molecular Medicine 2001, 7: 737-747. PMID: 11788787, PMCID: PMC1950004, DOI: 10.1007/bf03401963.Peer-Reviewed Original ResearchConceptsAdvanced glycation endproductsSerum advanced glycation endproductsDb/db miceNon-obese diabeticSerum AGEsMesangial cellsDb miceAGE-BSAGlycation endproductsIGF-I productionDiabetic renal damageSprague-Dawley ratsAGE clearanceSuppress macrophagesNOD miceDiabetic nephropathyRenal damageRenal excretionNormal ratsMMP-9Type IV collagenHost defense proteinsExcretionMRNA levelsMiceFibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo
Hartlapp I, Abe R, Saeed R, Peng T, Voelter W, Bucala R, Metz C. Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. The FASEB Journal 2001, 15: 2215-2224. PMID: 11641248, DOI: 10.1096/fj.01-0049com.Peer-Reviewed Original ResearchConceptsBlood vessel formationAngiogenic phenotypeVessel formationMesenchymal cell typesEndothelial cell invasionEndothelial cellsExtracellular matrix-degrading enzymesEndothelial cell migrationGrowth factorCellular microenvironmentMatrix-degrading enzymesCell invasionCell migrationCell typesCultured endothelial cellsTube formationHematopoietic growth factorsPromotion of angiogenesisPhenotypeAngiogenesis modelMicrovascular endothelial cellsCultured fibrocytesEnzymeAngiogenesisVivoPeripheral Blood Fibrocytes: Differentiation Pathway and Migration to Wound Sites
Abe R, Donnelly S, Peng T, Bucala R, Metz C. Peripheral Blood Fibrocytes: Differentiation Pathway and Migration to Wound Sites. The Journal Of Immunology 2001, 166: 7556-7562. PMID: 11390511, DOI: 10.4049/jimmunol.166.12.7556.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood CellsCell DifferentiationCell MovementCells, CulturedCollagenFemaleFibroblastsFibrosisGelsHumansInjections, IntravenousLipopolysaccharide ReceptorsMiceMice, Inbred BALB CReceptors, ChemokineStem Cell TransplantationStem CellsTransforming Growth Factor betaTransforming Growth Factor beta1Wound HealingConceptsCultured fibrocytesTissue injuryChemokine/chemokine receptor interactionsUnique cell surface phenotypeCutaneous tissue injurySecondary lymphoid chemokineAlpha-smooth muscle actinWound healingWound healing myofibroblastsMononuclear cell populationsCCR7 chemokine receptorChemokine receptor interactionsPotent immunostimulatory activitySmooth muscle actinCell surface phenotypeBlood-borne cellsDifferentiation pathwayFibrocyte traffickingLymphoid chemokinesFibrocyte differentiationChemokine receptorsT cellsSurface phenotypePotent stimulusMuscle actinRegulation of the CTL Response by Macrophage Migration Inhibitory Factor
Abe R, Peng T, Sailors J, Bucala R, Metz C. Regulation of the CTL Response by Macrophage Migration Inhibitory Factor. The Journal Of Immunology 2001, 166: 747-753. PMID: 11145646, DOI: 10.4049/jimmunol.166.2.747.Peer-Reviewed Original ResearchMeSH KeywordsAdjuvants, ImmunologicAdoptive TransferAnimalsAntibodies, MonoclonalCD8-Positive T-LymphocytesCell MovementCells, CulturedCytotoxicity Tests, ImmunologicCytotoxicity, ImmunologicFemaleInjections, IntraperitonealLymphocytes, Tumor-InfiltratingMacrophage Migration-Inhibitory FactorsMiceMice, Inbred C57BLNeoplasm TransplantationT-Lymphocytes, CytotoxicThymomaTumor Cells, CulturedConceptsMacrophage migration inhibitory factorMigration inhibitory factorTumor-bearing miceCTL activityCTL responsesT lymphocytesAnti-tumor T lymphocytesInhibitory factorCultures of splenocytesApoptotic tumor cellsT cell survivalIL-2RPivotal cytokineT cellsHistological examinationImmune responseIFN-gammaSplenocyte culturesAg stimulationMouse modelTumor growthTumor tissueTumor cellsMiceElevated expression