2022
The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging
Ryu S, Sidorov S, Ravussin E, Artyomov M, Iwasaki A, Wang A, Dixit VD. The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging. Immunity 2022, 55: 1609-1626.e7. PMID: 35963236, PMCID: PMC9474643, DOI: 10.1016/j.immuni.2022.07.007.Peer-Reviewed Original ResearchConceptsToll-like receptor 4ISG inductionMatricellular proteinPro-inflammatory phenotypeAnti-inflammatory macrophagesInterferon-stimulated gene expressionAdipocyte-specific deletionInhibition of glycolysisImmunometabolic adaptationsMyD88 pathwayReceptor 4Chronic diseasesFunctional declineCaloric restrictionInterferon responseHealth spanMacrophagesInflammationMitochondrial respirationSPARCInductionGene expressionAdipokinesObesityIFNCaloric restriction in humans reveals immunometabolic regulators of health span
Spadaro O, Youm Y, Shchukina I, Ryu S, Sidorov S, Ravussin A, Nguyen K, Aladyeva E, Predeus AN, Smith SR, Ravussin E, Galban C, Artyomov MN, Dixit VD. Caloric restriction in humans reveals immunometabolic regulators of health span. Science 2022, 375: 671-677. PMID: 35143297, PMCID: PMC10061495, DOI: 10.1126/science.abg7292.Peer-Reviewed Original ResearchMeSH Keywords1-Alkyl-2-acetylglycerophosphocholine EsteraseAdipose TissueAdultAgingAnimalsCaloric RestrictionDown-RegulationEnergy MetabolismFemaleHumansImmune SystemInflammasomesInflammationLongevityLymphopoiesisMacrophagesMaleMiceMiddle AgedMitochondriaNLR Family, Pyrin Domain-Containing 3 ProteinThermogenesisThymus GlandTranscriptomeConceptsCaloric restrictionAge-related inflammationHealth spanAnti-inflammatory responseNLRP3 inflammasome activationEctopic lipidsMetabolic healthInflammasome activationHealthy humansAdipose tissueImmunometabolic effectsFactor acetyl hydrolaseImmune defenseInflammationAcetyl hydrolaseMitochondrial bioenergeticsHumansLife spanLipoatrophyPLA2G7ThymopoiesisMice
2021
Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis
Zhang X, McDonald JG, Aryal B, Canfrán-Duque A, Goldberg EL, Araldi E, Ding W, Fan Y, Thompson BM, Singh AK, Li Q, Tellides G, Ordovás-Montanes J, García Milian R, Dixit VD, Ikonen E, Suárez Y, Fernández-Hernando C. Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2107682118. PMID: 34782454, PMCID: PMC8617522, DOI: 10.1073/pnas.2107682118.Peer-Reviewed Original ResearchConceptsCholesterol biosynthetic intermediatesBiosynthetic intermediatesDependent inflammasome activationSingle-cell transcriptomicsMitochondrial reactive oxygen species productionFoam cell formationMacrophage foam cellsReactive oxygen species productionHuman coronary artery lesionsConversion of desmosterolTranscriptomic analysisMacrophage cholesterol metabolismPhysiological contextOxygen species productionLiver X receptor ligandsApoptosis-associated speck-like proteinRetinoid X receptor activationX receptor ligandsInflammasome activationAtherosclerotic plaquesSpeck-like proteinCholesterol homeostasisMacrophage inflammasome activationKey moleculesCell formation
2020
Dietary Regulation of Immunity
Lee AH, Dixit VD. Dietary Regulation of Immunity. Immunity 2020, 53: 510-523. PMID: 32937152, PMCID: PMC7491384, DOI: 10.1016/j.immuni.2020.08.013.Peer-Reviewed Original ResearchConceptsDietary intakeOrganismal metabolismRestoration of homeostasisRegulation of glucoseMacronutrient intakeImmune regulationImmunological functionsImmunological responseImmunometabolic responsesMitochondrial respirationImmune systemInsulin actionDietary regulationProtein metabolismTissue functionIntakeDietary surplusRegulationVital functionsImmunityMetabolismHealthspanLeukocytesCheckpointHomeostasis
2019
Gaining Weight: Insulin-Eating Islet Macrophages
Spadaro O, Dixit VD. Gaining Weight: Insulin-Eating Islet Macrophages. Immunity 2019, 50: 13-15. PMID: 30650372, DOI: 10.1016/j.immuni.2018.12.026.Peer-Reviewed Original ResearchMeSH KeywordsCell ProliferationDiabetes Mellitus, Type 2HumansInflammationInsulinIslets of LangerhansMacrophagesObesity
2018
Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity
Ravussin A, Youm YH, Sander J, Ryu S, Nguyen K, Varela L, Shulman GI, Sidorov S, Horvath TL, Schultze JL, Dixit VD. Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity. Cell Reports 2018, 24: 1085-1092.e6. PMID: 30067966, PMCID: PMC6223120, DOI: 10.1016/j.celrep.2018.06.112.Peer-Reviewed Original ResearchConceptsHigh-fat dietInsulin resistanceFood intakeMetabolic inflammationNucleobindin-2M2-like macrophage polarizationHigh-fat diet feedingWeight lossAdipose tissue macrophagesObesity-associated diseasesNesfatin-1Insulin sensitivityDiet feedingMacrophage polarizationNUCB2 proteinMyeloid cellsTissue macrophagesGlobal deletionClassical M1NUCB2NFκB-dependent mannerWeight gainSatietyIntakeAdiposity
2017
Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing
Camell CD, Sander J, Spadaro O, Lee A, Nguyen KY, Wing A, Goldberg EL, Youm YH, Brown CW, Elsworth J, Rodeheffer MS, Schultze JL, Dixit VD. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 2017, 550: 119-123. PMID: 28953873, PMCID: PMC5718149, DOI: 10.1038/nature24022.Peer-Reviewed Original ResearchAdipocytesAdipose TissueAgingAnimalsCaspase 1CatecholaminesGene Expression ProfilingGene Expression RegulationGrowth Differentiation Factor 3InflammasomesLipaseLipolysisMacrophagesMiceMonoamine OxidaseMonoamine Oxidase InhibitorsNLR Family, Pyrin Domain-Containing 3 ProteinNorepinephrineSterol EsteraseIGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge
Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, Dixit VD. IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge. Cell Reports 2017, 19: 225-234. PMID: 28402847, PMCID: PMC5513500, DOI: 10.1016/j.celrep.2017.03.046.Peer-Reviewed Original ResearchConceptsMacrophage activationM2-like stateHelminth Nippostrongylus brasiliensisNormal insulin sensitivityAdipose tissue macrophagesHigh-fat dietM2-like macrophage activationTyrosine hydroxylase expressionM2-like macrophagesMacrophage activation phenotypeInsulin resistanceInsulin sensitivityHydroxylase expressionImmunometabolic responsesElevated adipositySpecific cytokinesKnockout miceAdipose tissueMacrophage phenotypeMyeloid cellsNippostrongylus brasiliensisTissue macrophagesPhagocytic activityIGF1 receptorCold challengeβ-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares
Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, Dixit VD. β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Reports 2017, 18: 2077-2087. PMID: 28249154, PMCID: PMC5527297, DOI: 10.1016/j.celrep.2017.02.004.Peer-Reviewed Original ResearchConceptsKetogenic dietGouty flaresΒ-hydroxybutyrateMajor risk factorAnti-inflammatory moleculesNLRP3-dependent mannerAlternate metabolic fuelsGout flaresJoint destructionIL-1βIntense painInterleukin-1βNLRP3 inflammasomeRisk factorsInflammatory neutrophilsBacterial infectionsNeutrophilsNLRP3Immune defenseGoutMetabolic fuelsBHBS100A9 fibrilsDietPainCarnitine acetyltransferase (CRAT) expression in macrophages is dispensable for nutrient stress sensing and inflammation
Goldberg EL, Dixit VD. Carnitine acetyltransferase (CRAT) expression in macrophages is dispensable for nutrient stress sensing and inflammation. Molecular Metabolism 2017, 6: 219-225. PMID: 28180063, PMCID: PMC5279934, DOI: 10.1016/j.molmet.2016.12.008.Peer-Reviewed Original ResearchConceptsNutrient stressFatty acid oxidationAcyl-CoA poolMacrophage energy metabolismAcid oxidationMetabolic stressorsMyeloid lineage cellsStress sensingSwitch mechanismMetabolic homeostasisLineage cellsEnergy metabolismImportant unanswered questionsMuscle cellsHomeostasisCRATHigh-fat diet-induced obesityAcetyltransferase expressionDiet-induced obesityGlucose homeostasisTissue leukocytosisMacrophagesCellsLittermate controlsUnanswered questions
2016
Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence
Spadaro O, Goldberg EL, Camell CD, Youm YH, Kopchick JJ, Nguyen KY, Bartke A, Sun LY, Dixit VD. Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence. Cell Reports 2016, 14: 1571-1580. PMID: 26876170, PMCID: PMC5992590, DOI: 10.1016/j.celrep.2016.01.044.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsAutocrine CommunicationBone Marrow CellsCarrier ProteinsGene Expression RegulationHomeostasisImmunity, InnateImmunologic MemoryInflammasomesInterferon-gammaLongevityMacrophagesMiceMice, KnockoutNLR Family, Pyrin Domain-Containing 3 ProteinReceptor, IGF Type 1Receptors, SomatotropinSignal TransductionSpleenT-LymphocytesConceptsNLRP3 inflammasome activationInflammasome activationImmune senescenceAge-related immune senescenceGrowth hormone receptor deficiencyHigher IFNγ secretionNaive T lymphocytesImmune system homeostasisMyeloid lineage cellsEffector memoryIFNγ secretionInflammasome inhibitionEffector cellsChronic inflammationReceptor deficiencyAdvanced ageAge-related activationSystemic activationT lymphocytesGrowth hormone receptorNLRP3 ligandsInnate immuneSomatotropic axisSystem homeostasisNLRP3
2015
A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents
Kursawe R, Dixit VD, Scherer PE, Santoro N, Narayan D, Gordillo R, Giannini C, Lopez X, Pierpont B, Nouws J, Shulman GI, Caprio S. A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 2015, 65: 610-618. PMID: 26718495, PMCID: PMC4764142, DOI: 10.2337/db15-1478.Peer-Reviewed Original ResearchMeSH KeywordsAbdomenAcetyl-CoA CarboxylaseAdipogenesisAdiponectinAdolescentCarrier ProteinsCaspase 1ChildDown-RegulationFatty Acid Synthase, Type IFemaleGene Expression ProfilingGlucose Transporter Type 4HumansInflammasomesInsulin ResistanceInterleukin-1betaIntra-Abdominal FatLeptinLipogenesisLipoprotein LipaseMacrophagesMagnetic Resonance ImagingMaleNLR Family, Pyrin Domain-Containing 3 ProteinObesityPPAR gammaSirtuin 1Sterol Regulatory Element Binding Protein 1Subcutaneous FatToll-Like Receptor 4ConceptsVisceral adipose tissueObese adolescentsInsulin resistanceTissue inflammationNLRP3 inflammasomeAdipose tissueInnate immune cell sensorsAbdominal subcutaneous adipose tissueAbdominal adipose depotsAbdominal fat partitioningAdipogenesis/lipogenesisAdipose tissue inflammationProinflammatory cytokines interleukinInfiltration of macrophagesExpression of CASP1Subcutaneous adipose tissueInflammation markersSAT biopsiesIL-18Macrophage infiltrationVisceral fatCytokines interleukinSAT ratioInsulin sensitivityAdipose depots
2014
Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity
Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, Dragoljevic D, Hong ES, Abdel-Latif A, Smyth SS, Choi SH, Korner J, Bornfeldt KE, Fisher EA, Dixit VD, Tall AR, Goldberg IJ, Murphy AJ. Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity. Cell Metabolism 2014, 19: 821-835. PMID: 24807222, PMCID: PMC4048939, DOI: 10.1016/j.cmet.2014.03.029.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBone MarrowCarrier ProteinsCell ProliferationHumansInflammasomesInterleukin-1betaMacrophagesMaleMiceMice, Inbred C57BLMonocytesMyeloid Differentiation Factor 88MyelopoiesisNeutrophilsNLR Family, Pyrin Domain-Containing 3 ProteinObesityReceptors, Interleukin-1Toll-Like Receptor 4ConceptsAT macrophagesInsulin resistanceNLRP3 inflammasome-dependent IL-1β productionAdipose tissueMyeloid progenitorsTLR4/MyD88Infiltration of macrophagesBone marrow myeloid progenitorsIL-1β productionS100A8/A9IL-1 receptorMarrow myeloid progenitorsProduction of monocytesAT inflammationLean recipientsNLRP3-ILTLR4 ligandIL-1βMurine modelMyeloid progenitor proliferationProminent monocytosisObesityMonocytosisWeight lossProgenitor proliferationInactivation of C/ebp Homologous Protein-driven Immune-Metabolic Interactions Exacerbate Obesity and Adipose Tissue Leukocytosis*
Grant R, Nguyen KY, Ravussin A, Albarado D, Youm YH, Dixit VD. Inactivation of C/ebp Homologous Protein-driven Immune-Metabolic Interactions Exacerbate Obesity and Adipose Tissue Leukocytosis*. Journal Of Biological Chemistry 2014, 289: 14045-14055. PMID: 24662293, PMCID: PMC4022874, DOI: 10.1074/jbc.m113.545921.Peer-Reviewed Original ResearchConceptsAblation of CHOPChronic caloric excessHigh-fat dietInsulin resistanceFat dietCaloric excessTissue leukocytosisTissue macrophagesChronic positive energy balanceActivation of ILHigher insulin resistanceImportant molecular mediatorAdipose tissue macrophagesCHOP-deficient miceImmune-metabolic interactionsTranscription factor C/EBP homologous proteinC/EBP homologous proteinSensitivity of macrophagesEndoplasmic reticulum stressHealthy obesityFrequency of M1Inflammatory mechanismsMetabolic inflammationImmune activationPositive energy balance