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 infectionHigher serum MIF levelsHigh-expression MIF allelesRetrospective 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
CD74 promotes the formation of an immunosuppressive tumor microenvironment in triple-negative breast cancer in mice by inducing the expansion of tolerogenic dendritic cells and regulatory B cells.
Pellegrino B, David K, Rabani S, Lampert B, Tran T, Doherty E, Piecychna M, Meza-Romero R, Leng L, Hershkovitz D, Vandenbark A, Bucala R, Becker-Herman S, Shachar I. CD74 promotes the formation of an immunosuppressive tumor microenvironment in triple-negative breast cancer in mice by inducing the expansion of tolerogenic dendritic cells and regulatory B cells. PLOS Biology 2024, 22: e3002905. PMID: 39576827, DOI: 10.1371/journal.pbio.3002905.Peer-Reviewed Original ResearchTriple-negative breast cancerMacrophage migration inhibitory factorImmunosuppressive tumor microenvironmentTolerogenic dendritic cellsRegulatory B cellsChronic lymphocytic leukemiaTumor microenvironmentDendritic cellsImmune cellsB cellsBreast cancerInfiltration of immune cellsAggressive breast cancer subtypeMassive infiltration of immune cellsLevels of CD74Cytokine macrophage migration inhibitory factorBreast cancer subtypesMigration inhibitory factorBinding to CD74Naive BTol-DCsLymphocytic leukemiaTumor environmentMassive infiltrationCancer subtypesPrognostic 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 sequencingDownregulation 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 tissueA small-molecule allele-selective transcriptional inhibitor of the MIF immune susceptibility locus
Li J, Leng L, Pantouris G, Manjula R, Piecychna M, Abriola L, Hu B, Lolis E, Armstrong M, Donnelly S, Bucala R. A small-molecule allele-selective transcriptional inhibitor of the MIF immune susceptibility locus. Journal Of Biological Chemistry 2024, 300: 107443. PMID: 38838773, PMCID: PMC11259703, DOI: 10.1016/j.jbc.2024.107443.Peer-Reviewed Original ResearchPromoter microsatellitesGene expressionMicrosatellite repeat numberMacrophage migration inhibitory factorLength-dependent mannerRNA expression analysisSusceptibility lociFunctional variantsSmall molecule inhibitorsExpression analysisPharmacogenomic developmentRepeat numberMicrosatelliteFunctional interactionsTranscription inhibitorInflammatory gene expressionMIF mRNA expressionCytokine macrophage migration inhibitory factorTranscriptionGenesProtein expressionMigration inhibitory factorExpressionInhibitory factorExpressing macrophagesMacrophage-derived macrophage migration inhibitory factor mediates renal injury in anti-glomerular basement membrane glomerulonephritis
Yang H, Li J, Huang X, Bucala R, Xu A, Lan H. Macrophage-derived macrophage migration inhibitory factor mediates renal injury in anti-glomerular basement membrane glomerulonephritis. Frontiers In Immunology 2024, 15: 1361343. PMID: 38846956, PMCID: PMC11153660, DOI: 10.3389/fimmu.2024.1361343.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorMigration inhibitory factorTreatment of immune-mediated kidney diseasesMacrophage MIFMIF depletionPathogenic roleSource of MIFImmune-mediated kidney diseasesAnti-glomerular basement membrane glomerulonephritisInhibitory factorT cell recruitmentGlomerular crescent formationTh17 immune responsesReduced serum creatininePolarization of macrophagesRenal macrophagesSerum creatinineCrescentic glomerulonephritisInhibiting Th1Renal injuryControl miceCreatine clearanceCrescent formationMembranous glomerulonephritisConditional ablationMIF-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 4A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation
Wang H, Slotabec L, Didik S, Li Z, Leng L, Zhao B, Bucala R, Li J. A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation. Metabolism 2024, 153: 155792. PMID: 38232801, PMCID: PMC10932879, DOI: 10.1016/j.metabol.2024.155792.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorActivating AMP-activated protein kinaseI/R stressAging heartMacrophage migration inhibitory factor expressionCardiac metabolic profileReactive oxygen speciesIschemia-reperfusion insultIschemia-reperfusion (I/RAMP-activated protein kinaseMIF signalingMigration inhibitory factorDecreased myocardial infarct sizeAccumulation of reactive oxygen speciesMyocardial infarct sizeSystolic functionInnate cytokinesPharmacological augmentationSenescent heartsAged myocardiumSenescent myocardiumAge-related reductionIschemia-reperfusionI/R injuryMetabolic profileMIF 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 ResearchConceptsBrain 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 therapeuticsMacrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review
Jarmula J, Lee J, Lauko A, Rajappa P, Grabowski M, Dhawan A, Chen P, Bucala R, Vogelbaum M, Lathia J. Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review. Neuro-Oncology Advances 2024, 6: vdae142. PMID: 39233830, PMCID: PMC11372298, DOI: 10.1093/noajnl/vdae142.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorPrimary CNS tumorsCentral nervous systemMigration inhibitory factorCNS tumorsPrimary central nervous systemInhibitory factorTherapeutic targetPre-clinical studiesFunctions of macrophage migration inhibitory factorPreclinical modelsImmune evasionSmall molecule inhibitorsNeuro-oncologyClinical trialsTumor initiationClinical translationMonoclonal antibodiesTumorigenic processNervous systemTherapeutic requirementsCell proliferationTherapeutic developmentTumorEffective target
2023
Extracellular macrophage migration inhibitory factor (MIF) downregulates adipose hormone-sensitive lipase (HSL) and contributes to obesity
Chen L, Li L, Cui D, Huang Y, Tong H, Zabihi H, Wang S, Qi Y, Lakowski T, Leng L, Liu S, Wu H, Young L, Bucala R, Qi D. Extracellular macrophage migration inhibitory factor (MIF) downregulates adipose hormone-sensitive lipase (HSL) and contributes to obesity. Molecular Metabolism 2023, 79: 101834. PMID: 37935315, PMCID: PMC10700858, DOI: 10.1016/j.molmet.2023.101834.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorExtracellular MIFHigh-fat dietHormone-sensitive lipaseDevelopment of obesityMigration inhibitory factorInhibitory factorRole of cytokinesExtracellular actionJNK phosphorylationMIF levelsSevere obesityHFD miceHFD feedingMIF antibodyWT miceAdipocyte hypertrophyCOP9 signalosome subunit 5Fat dietHSL expressionObesityAutocrine fashionHSL activationSensitive lipaseInhibitory action830 Inhibition of macrophage migration inhibitory factor (MIF) to overcome immune checkpoint resistance in melanoma
Sanchez-Zuno G, Caulfield J, Leng L, Zhang L, Jilaveanu L, Kluger H, Bucala R, Tran T. 830 Inhibition of macrophage migration inhibitory factor (MIF) to overcome immune checkpoint resistance in melanoma. 2023, a928-a928. DOI: 10.1136/jitc-2023-sitc2023.0830.Peer-Reviewed Original ResearchMacrophage 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 deletionCytokinesCancerThe 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 ResearchConceptsMacrophage migration inhibitory factorImmune activationCytokine macrophage migration inhibitory factorMigration inhibitory factorLactotransferrin (LTF) expressionLeukocyte infiltrationHallmark of glioblastomaImmune microenvironmentTreatment responseRs755622Inhibitory factorDrug resistanceGermline mutationsIntratumoral heterogeneityTumoral microenvironmentGermline SNPsGlioblastomaUrothelial 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
CD74 as a regulator of transcription in normal B cells
David K, Friedlander G, Pellegrino B, Radomir L, Lewinsky H, Leng L, Bucala R, Becker-Herman S, Shachar I. CD74 as a regulator of transcription in normal B cells. Cell Reports 2022, 41: 111572. PMID: 36323260, DOI: 10.1016/j.celrep.2022.111572.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorNormal B cellsB cellsCytokine macrophage migration inhibitory factorRegulators of transcriptionChronic lymphocytic leukemia cellsMigration inhibitory factorNovel therapeutic pathwaysInhibition of transcriptionLymphocytic leukemia cellsTumor suppressor geneTranscriptional regulatorsTranscription factorsTherapeutic pathwaysCLL cellsFuture treatmentIntracellular domainOncogenic transformationMalignant cellsInhibitory factorRegulatory functionsPromoter areaLeukemia cellsTranscriptionGenesMacrophage 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 tissueBladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice
Ye S, Ma F, Mahmood DFD, Meyer-Siegler KL, Leng L, Bucala R, Vera PL. Bladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice. Frontiers In Systems Neuroscience 2022, 16: 882493. PMID: 35645739, PMCID: PMC9135998, DOI: 10.3389/fnsys.2022.882493.Peer-Reviewed Original ResearchHigh mobility group box 1Macrophage migration inhibitory factorBladder painIntravesical fluidOxidative stressLevels of HMGB1Mobility group box 1Bladder oxidative stressFemale C57BL/6 miceMigration inhibitory factorGroup box 1Possible therapeutic strategiesN-acetylcysteine amideBladder edemaMIF antagonismMIF deficiencyHMGB1 concentrationsMicturition frequencyMicturition volumeMIF releaseHMGB1 levelsC57BL/6 miceMicturition parametersHistological signsHistological evidenceMacrophage 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. The 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