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
Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma
Valdez C, Sánchez-Zuno G, Osmani L, Ibrahim W, Galan A, Bacchiocchi A, Halaban R, Kulkarni R, Kang I, Bucala R, Tran T. Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma. Oncotarget 2024, 15: 507-520. PMID: 39028303, PMCID: PMC11259151, DOI: 10.18632/oncotarget.28615.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigens, Differentiation, B-LymphocyteBiomarkers, TumorFemaleHistocompatibility Antigens Class IIHumansImmune Checkpoint InhibitorsIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMaleMelanomaMiddle AgedMutationPrognosisRetrospective StudiesSkin NeoplasmsConceptsMacrophage migration inhibitory factorImmune checkpoint inhibitionD-dopachrome tautomeraseExpression of macrophage migration inhibitory factorDrivers of tumor progressionInflammatory cell markersPatient tumor samplesPatient survival outcomesMigration inhibitory factorStatistically significant differenceCheckpoint inhibitionImmune therapyPrognostic valueSurvival outcomesResistant melanomaGene expressionImproved survivalRetrospective studyInflammatory markersTumor progressionCell markersTumor samplesClinical evidenceMelanomaBulk RNA sequencingMacrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities
Valdez C, Sánchez-Zuno G, Bucala R, Tran T. Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities. International Journal Of Molecular Sciences 2024, 25: 4849. PMID: 38732068, PMCID: PMC11084905, DOI: 10.3390/ijms25094849.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCarcinogenesisHumansIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsNeoplasmsSignal TransductionConceptsInhibition of MIFResponse to infectionNon-canonical signaling pathwaysClinical studiesCancer patientsClinical trialsInflammatory cytokinesDriving tumorigenesisClinical explorationCancer typesCancerDual inhibitionTherapeutic targetIn vivoIn vitroSignaling pathwayMIFAntitumor candidateBinding partnersMIF-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 4MIF contribution to progressive brain diseases
Matejuk A, Benedek G, Bucala R, Matejuk S, Offner H, Vandenbark A. MIF contribution to progressive brain diseases. Journal Of Neuroinflammation 2024, 21: 8. PMID: 38178143, PMCID: PMC10765708, DOI: 10.1186/s12974-023-02993-6.Peer-Reviewed Original ResearchMeSH KeywordsBrain DiseasesCalgranulin ACalgranulin BHumansInflammationIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMultiple SclerosisNervous System DiseasesConceptsBrain diseasesMultiple sclerosisAlzheimer's diseaseMacrophage migration inhibitory factorModulation of neuroinflammationNumerous neurologic diseasesMigration inhibitory factorProgressive brain diseaseNew therapeutic strategiesInflammatory mediatorsChronic inflammationAutoimmune diseasesVascular diseaseNervous system developmentNeurologic diseaseNeuroendocrine functionPsychiatric disordersTherapeutic strategiesEconomic burdenNeurological diseasesNew biomarkersInhibitory factorNeurodegenerative pathologiesDiseaseNovel therapeutics
2023
The SNP rs755622 is associated with immune activation in glioblastoma
Alban T, Grabowski M, Otvos B, Bayik D, Wang W, Zalavadia A, Makarav V, Troike K, McGraw M, Rabljenovic A, Lauko A, Neumann C, Roversi G, Waite K, Cioffi G, Patil N, Tran T, McCortney K, Steffens A, Diaz-Montero C, Brown J, Egan K, Horbinski C, Barnholtz-Sloan J, Rajappa P, Vogelbaum M, Bucala R, Chan T, Ahluwalia M, Lathia J. The SNP rs755622 is associated with immune activation in glioblastoma. JCI Insight 2023, 8: e160024. PMID: 37252795, PMCID: PMC10371339, DOI: 10.1172/jci.insight.160024.Peer-Reviewed Original ResearchMeSH KeywordsGlioblastomaHumansIntramolecular OxidoreductasesLactoferrinMacrophage Migration-Inhibitory FactorsPolymorphism, Single NucleotidePromoter Regions, GeneticTumor MicroenvironmentConceptsMacrophage migration inhibitory factorImmune activationCytokine macrophage migration inhibitory factorMigration inhibitory factorLactotransferrin (LTF) expressionLeukocyte infiltrationHallmark of glioblastomaImmune microenvironmentTreatment responseRs755622Inhibitory factorDrug resistanceGermline mutationsIntratumoral heterogeneityTumoral microenvironmentGermline SNPsGlioblastoma
2022
Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection
Trifone C, Baquero L, Czernikier A, Benencio P, Leng L, Laufer N, Quiroga MF, Bucala R, Ghiglione Y, Turk G. Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection. Viruses 2022, 14: 2218. PMID: 36298774, PMCID: PMC9611675, DOI: 10.3390/v14102218.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorMIF stimulationMIF treatmentIL-17AHIV infectionMIF/CD74 axisFounder HIV-1Functionality of CD4Higher IL-17AHigher MIF concentrationsMIF plasma levelsHIV-1 infectionMigration inhibitory factorPossible therapeutic targetMIF concentrationsIntracellular cytokinesR5-tropicCytokine productionIL-1βIL-6IL-8Plasma levelsHealthy donorsViral persistenceT lymphocytes“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 tissue
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 macrophagesICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus
Yao J, Leng L, Fu W, Li J, Bronner C, Bucala R. ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus. Arthritis & Rheumatology 2021, 73: 1931-1942. PMID: 33844457, DOI: 10.1002/art.41753.Peer-Reviewed Original ResearchMeSH KeywordsAllelesApoptosisCCAAT-Enhancer-Binding ProteinsCell LineFibroblastsGene Expression RegulationGenetic LociGenetic Predisposition to DiseaseGenotypeGlucocorticoidsHumansIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsPromoter Regions, GeneticReceptors, GlucocorticoidUbiquitin-Protein LigasesConceptsMacrophage migration inhibitory factorAutoimmune disease severityMIF -794 CATTRheumatoid synovial fibroblastsMIF expressionGlucocorticoid receptorGlucocorticoid sensitivitySynovial fibroblastsT cellsDisease severityPeripheral blood T cellsBlood T cellsMigration inhibitory factorGlucocorticoid-treated cellsAP-1Glucocorticoid immunosuppressionMIF promoterMIF genotypeMIF polymorphismsFactor antibodyInflammatory responseT lymphocytesActivator protein-1Glucocorticoid responsivenessInhibitory factorRole 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 factorCD74 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 maintenanceHsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer
Klemke L, De Oliveira T, Witt D, Winkler N, Bohnenberger H, Bucala R, Conradi LC, Schulz-Heddergott R. Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer. Cell Death & Disease 2021, 12: 155. PMID: 33542244, PMCID: PMC7862487, DOI: 10.1038/s41419-021-03426-z.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenic ProteinsAnimalsAntigens, Differentiation, B-LymphocyteAntineoplastic AgentsColitis-Associated NeoplasmsDisease Models, AnimalFemaleHCT116 CellsHEK293 CellsHistocompatibility Antigens Class IIHSP90 Heat-Shock ProteinsHumansInflammation MediatorsIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMaleMice, Inbred C57BLMice, KnockoutNeovascularization, PathologicOrganoidsProtein StabilitySignal TransductionTumor BurdenTumor-Associated MacrophagesConceptsMacrophage migration inhibitory factorMIF levelsMacrophage recruitmentAction of MIFColitis-associated colorectal cancer (CAC) mouse modelTumor growthTumor progressionFunction of MIFColorectal cancer mouse modelHigher MIF levelsHost inflammatory pathwaysTumor-specific functionsEpithelial cellsShorter overall survivalCRC tumor progressionClinical correlation studiesMigration inhibitory factorCRC tumor growthCancer mouse modelWild-type organoidsTumor epithelial cellsHSP90 inhibitor treatmentCD74 expressionOverall survivalCRC patients
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
1999
Inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity by dopachrome analogs
Zhang X, Bucala R. Inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity by dopachrome analogs. Bioorganic & Medicinal Chemistry Letters 1999, 9: 3193-3198. PMID: 10576686, DOI: 10.1016/s0960-894x(99)00561-2.Peer-Reviewed Original ResearchMeSH KeywordsIndolequinonesIndolesIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsQuinones
1997
Biochemical and Mutational Investigations of the Enzymatic Activity of Macrophage Migration Inhibitory Factor †
Bendrat K, Al-Abed Y, Callaway D, Peng T, Calandra T, Metz C, Bucala R. Biochemical and Mutational Investigations of the Enzymatic Activity of Macrophage Migration Inhibitory Factor †. Biochemistry 1997, 36: 15356-15362. PMID: 9398265, DOI: 10.1021/bi971153a.Peer-Reviewed Original ResearchConceptsEnzymatic activityL-dopachrome methyl esterN-terminal proline residueSite-directed mutagenesisAmino acid residuesDopachrome tautomerase activityNative solution conditionsMutant proteinsProtein domainsStable trimer formationCarboxy terminusBasic residuesN-terminusProline residuesSDS-PAGE analysisBacterial enzymesHomotrimeric structureAcid residuesCatalytic functionEnzymatic mechanismMutational investigationTrimer formationLow protein concentrationsBiochemical analysisInternal histidine