2024
Single-Cell Analysis Reveals a Subset of High IL-12p40-Secreting Dendritic Cells within Mouse Bone Marrow-Derived Macrophages Differentiated with M-CSF.
Bridges K, Pizzurro G, Khunte M, Chen M, Salvador Rocha E, Alexander A, Bass V, Kellman L, Baskaran J, Miller-Jensen K. Single-Cell Analysis Reveals a Subset of High IL-12p40-Secreting Dendritic Cells within Mouse Bone Marrow-Derived Macrophages Differentiated with M-CSF. The Journal Of Immunology 2024, 212: 1357-1365. PMID: 38416039, DOI: 10.4049/jimmunol.2300431.Peer-Reviewed Original ResearchBone marrow-derived macrophagesDendritic cellsCell-to-cell heterogeneitySingle-cell RNA sequencing dataRNA sequencing dataSingle-cell analysisIL-12p40Sequence dataExpression of IL12BInnate immune functionProduction of IL-12Bone marrow-derived macrophage culturesMurine bone marrow-derived macrophagesSurface marker expressionAcute inflammatory responseMarrow-derived macrophagesGene encoding IL-12p40Secretion assayIL12B expressionReporter miceDC lineageIL-12GenesProinflammatory cytokinesM-CSF
2023
Apoptosis recognition receptors regulate skin tissue repair in mice
Justynski O, Bridges K, Krause W, Forni M, Phan Q, Sandoval-Schaefer T, Carter K, King D, Hsia H, Gazes M, Vyce S, Driskell R, Miller-Jensen K, Horsley V. Apoptosis recognition receptors regulate skin tissue repair in mice. ELife 2023, 12: e86269. PMID: 38127424, PMCID: PMC10735221, DOI: 10.7554/elife.86269.Peer-Reviewed Original ResearchA bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Djureinovic D, Weiss S, Krykbaeva I, Qu R, Vathiotis I, Moutafi M, Zhang L, Perdigoto A, Wei W, Anderson G, Damsky W, Hurwitz M, Johnson B, Schoenfeld D, Mahajan A, Hsu F, Miller-Jensen K, Kluger Y, Sznol M, Kaech S, Bosenberg M, Jilaveanu L, Kluger H. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Molecular Cancer 2023, 22: 182. PMID: 37964379, PMCID: PMC10644655, DOI: 10.1186/s12943-023-01884-x.Peer-Reviewed Original ResearchConceptsStable diseasePartial responseMacrophage populationsThree-drug regimenUnconfirmed partial responsePhase I trialLimited treatment optionsMonocyte/macrophage populationNon-classical monocytesMurine melanoma modelTreatment-related changesResultsThirteen patientsWorse survivalI trialInflammatory tumorPatient populationTreatment optionsImmune cellsDisease progressionMurine studiesPreclinical modelsResistant melanomaAntigen presentationMurine modelCyTOF analysisReframing macrophage diversity with network motifs
Pizzurro G, Miller-Jensen K. Reframing macrophage diversity with network motifs. Trends In Immunology 2023, 44: 965-970. PMID: 37949786, PMCID: PMC11057955, DOI: 10.1016/j.it.2023.10.009.Commentaries, Editorials and LettersConceptsNetwork motifsDistinct biological functionsSystems biology conceptsMacrophage stateMacrophage responseBiological functionsMacrophage diversityExtracellular networkMacrophage activationDisease contextsMotifLocal molecular interactionsMolecular interactionsFunctional modulesBiology conceptsDiversityActivationTissueIntracellularResponseCombinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance.
Krykbaeva I, Bridges K, Damsky W, Pizzurro G, Alexander A, McGeary M, Park K, Muthusamy V, Eyles J, Luheshi N, Turner N, Weiss S, Olino K, Kaech S, Kluger H, Miller-Jensen K, Bosenberg M. Combinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance. Cancer Immunology Research 2023, 11: 1332-1350. PMID: 37478171, DOI: 10.1158/2326-6066.cir-22-0699.Peer-Reviewed Original ResearchConceptsPD-1 resistanceDendritic cellsTumor regressionAnti-PD-1 resistanceActivates Dendritic CellsCytokine secretion profilingSystemic cytokine profileTriple therapy combinationInnate immune activationAdaptive immune responsesComplete tumor regressionMajority of miceSignificant clinical challengeMouse melanoma modelT cell activationAgonistic CD40Checkpoint inhibitorsDC subsetsTriple therapyCytokine profileImmune activationCombinatorial immunotherapyTherapy combinationsT cellsClinical challengeFunctionally and Metabolically Divergent Melanoma-Associated Macrophages Originate from Common Bone-Marrow Precursors
Pizzurro G, Bridges K, Jiang X, Vidyarthi A, Miller-Jensen K, Colegio O. Functionally and Metabolically Divergent Melanoma-Associated Macrophages Originate from Common Bone-Marrow Precursors. Cancers 2023, 15: 3330. PMID: 37444440, PMCID: PMC10341323, DOI: 10.3390/cancers15133330.Peer-Reviewed Original ResearchGene Set Enrichment AnalysisBone marrow precursorsTissue-specific nichesTumor-associated macrophagesMelanoma tumor microenvironmentTranscriptomic analysisRNA sequencingTumor microenvironmentEnrichment analysisOxidative phosphorylationProtein secretionTemporal divergenceCanonical markersPolyamine metabolismTAM subsetsLike phenotypeSkin-resident macrophagesMacrophage phenotypeMonocytic precursorsOntogenyTumor progressionDepth characterizationPhenotypeMacrophage subsetsTAM subpopulations
2022
Langerhans cells are essential components of the angiogenic niche during murine skin repair
Wasko R, Bridges K, Pannone R, Sidhu I, Xing Y, Naik S, Miller-Jensen K, Horsley V. Langerhans cells are essential components of the angiogenic niche during murine skin repair. Developmental Cell 2022, 57: 2699-2713.e5. PMID: 36493773, PMCID: PMC10848275, DOI: 10.1016/j.devcel.2022.11.012.Peer-Reviewed Original ResearchConceptsAngiogenic nicheSingle-cell RNA sequencingLangerhans cellsControl of angiogenesisCanonical roleMouse geneticsPre-existing vesselsRNA sequencingImmune cellsSkin repairFunction of LCSkin-resident immune cellsNew blood vesselsMouse skin woundsThree-dimensional microscopyNicheNon-healing woundsEndothelial cellsAngiogenesisCellsCell immunityTreatment optionsInflammatory diseasesAntigen presentationInjury repairA transcriptional cycling model recapitulates chromatin-dependent features of noisy inducible transcription
Bullock ME, Moreno-Martinez N, Miller-Jensen K. A transcriptional cycling model recapitulates chromatin-dependent features of noisy inducible transcription. PLOS Computational Biology 2022, 18: e1010152. PMID: 36084132, PMCID: PMC9491597, DOI: 10.1371/journal.pcbi.1010152.Peer-Reviewed Original ResearchConceptsGene expression noiseExpression noiseTranscriptional burstingPromoter statesDifferent chromatin environmentsChromatin environmentChromatin statePause releaseTranscription factor NFChromatin accessibilityChromatin remodelingTranscriptional noiseChromatin locationsInducible transcriptionSubstantial phenotypic heterogeneityTranscriptional activationTranscription factorsTranscript distributionPolymerase complexTarget genesPolymerase bindingGene expressionPromoter activityViral activationBiological processesMapping and Validation of scRNA-Seq-Derived Cell-Cell Communication Networks in the Tumor Microenvironment
Bridges K, Miller-Jensen K. Mapping and Validation of scRNA-Seq-Derived Cell-Cell Communication Networks in the Tumor Microenvironment. Frontiers In Immunology 2022, 13: 885267. PMID: 35572582, PMCID: PMC9096838, DOI: 10.3389/fimmu.2022.885267.Peer-Reviewed Original ResearchConceptsScRNA-seqHigh-throughput transcriptional profilingCell-cell communication networksSingle-cell RNA sequencingCell-cell communicationSingle-cell technologiesCell-cell interactionsTumor microenvironmentTranscriptional profilingInteraction networksRNA sequencingBiological systemsNetwork analysisComputational approach
2021
3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype
Pizzurro GA, Liu C, Bridges K, Alexander AF, Huang A, Baskaran JP, Ramseier J, Bosenberg MW, Mak M, Miller-Jensen K. 3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype. Cancers 2021, 13: 4579. PMID: 34572807, PMCID: PMC8471848, DOI: 10.3390/cancers13184579.Peer-Reviewed Original ResearchTumor-associated macrophagesMelanoma tumor microenvironmentTumor microenvironmentTumor-promoting phenotypeAnti-tumor activityImmunosuppressive stateDisease progressionCo-culture systemImmune responseImmune activitySecretion profileDirect cell-cell interactionsMelanoma tumorsStromal componentsMacrophage transitionStromal cellsTumor cellsMelanoma cellsSingle-cell secretion analysis reveals a dual role for IL-10 in restraining and resolving the TLR4-induced inflammatory response
Alexander AF, Kelsey I, Forbes H, Miller-Jensen K. Single-cell secretion analysis reveals a dual role for IL-10 in restraining and resolving the TLR4-induced inflammatory response. Cell Reports 2021, 36: 109728. PMID: 34551303, PMCID: PMC8995750, DOI: 10.1016/j.celrep.2021.109728.Peer-Reviewed Original ResearchTNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes
Bass VL, Wong VC, Bullock ME, Gaudet S, Miller‐Jensen K. TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes. Molecular Systems Biology 2021, 17: msb202010127. PMID: 34288498, PMCID: PMC8290835, DOI: 10.15252/msb.202010127.Peer-Reviewed Original ResearchConceptsNF-κB-regulated inflammatory genesGene expression noiseOpen chromatin environmentTranscriptional burst sizeNF-κB target genesNF-κB-regulated genesHistone 3 acetylationChromatin environmentTranscription factor NF-κBTranscriptional noiseExpression noiseTranscriptional burstingTranscript distributionFactor NF-κBGene promoterSubset of cellsIntercellular heterogeneityTNF stimulationCell heterogeneityGenesTNF protein expressionTNF activationProtein expressionTranscriptionBurst sizeCo-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells
Muñoz-Rojas AR, Kelsey I, Pappalardo JL, Chen M, Miller-Jensen K. Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells. Nature Communications 2021, 12: 301. PMID: 33436596, PMCID: PMC7804107, DOI: 10.1038/s41467-020-20540-2.Peer-Reviewed Original ResearchConceptsCo-stimulated macrophagesFunctional diversitySingle-cell RNA sequencingGlobal transcriptional programSuch functional diversityTranscriptional programsTissue homeostasisRNA sequencingEnvironmental cuesGene resultsExclusive expressionInflammatory stimuli LPSCell heterogeneityIndividual cellsPolarization cuesIndividual macrophagesTissue repairCytokine genesDiversityInnate immune cellsFighting infectionsCellsMacrophagesCuesTranscription
2019
Microfluidic platform enables live-cell imaging of signaling and transcription combined with multiplexed secretion measurements in the same single cells
Ramji R, Alexander AF, Muñoz-Rojas AR, Kellman LN, Miller-Jensen K. Microfluidic platform enables live-cell imaging of signaling and transcription combined with multiplexed secretion measurements in the same single cells. Integrative Biology 2019, 11: 142-153. PMID: 31242304, PMCID: PMC8672722, DOI: 10.1093/intbio/zyz013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesCell CommunicationChemokine CCL2Chemokine CCL3Chemokine CCL5Equipment DesignLab-On-A-Chip DevicesLipopolysaccharidesMacrophagesMiceMice, Inbred C57BLMicrofluidicsRAW 264.7 CellsSignal TransductionTranscription Factor RelATranscription, GeneticTumor Necrosis Factor-alphaConceptsLive-cell imagingCell variabilitySame single cellSingle-cell assaysTranscription dynamicsBacterial component lipopolysaccharideDownstream responsesPathogenic assaultFluorescent reportersProtein secretionSingle cellsCell processesBiological sourcesCCL3 secretionRelative levelsCellsInnate immune cellsTranslocation dynamicsBiological stepC secretionTranscriptionSecretionCCL5 secretionRelAReporterFold-Change Detection of NF-κB at Target Genes with Different Transcript Outputs
Wong VC, Mathew S, Ramji R, Gaudet S, Miller-Jensen K. Fold-Change Detection of NF-κB at Target Genes with Different Transcript Outputs. Biophysical Journal 2019, 116: 709-724. PMID: 30704857, PMCID: PMC6382958, DOI: 10.1016/j.bpj.2019.01.011.Peer-Reviewed Original ResearchConceptsFold-change detectionTarget genesTranscript outputStress-responsive gene transcriptionSingle-cell dataNF-κB target genesRelA nuclear translocationLive-cell imagingMicrofluidic cell-trapping deviceLow-abundance transcriptsTranscription factor nuclear factorNF-κBRNA FISHTranscriptional outputΚB motifTranscript abundanceGene transcriptionTranscriptionTranscript numbersCell trap deviceJurkat TCell typesGenesNF-κB signalingMultiple biological mechanisms
2018
Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair
Shook BA, Wasko RR, Rivera-Gonzalez GC, Salazar-Gatzimas E, López-Giráldez F, Dash BC, Muñoz-Rojas AR, Aultman KD, Zwick RK, Lei V, Arbiser JL, Miller-Jensen K, Clark DA, Hsia HC, Horsley V. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 2018, 362 PMID: 30467144, PMCID: PMC6684198, DOI: 10.1126/science.aar2971.Peer-Reviewed Original ResearchConceptsDifferential gene expressionAdipocyte precursorsExtracellular matrix moleculesGene expressionTransplantation assaysMatrix moleculesFactor C.Factor 1Insulin-like growth factor-1Cell populationsTissue resilienceDistinct subpopulationsGrowth factor-1Profibrotic cellsTissue repairMultiple mouse modelsECM depositionSkin repairTissue dysfunctionProliferationMouse modelMyofibroblastsWoundingMacrophagesRepairUsing data to guide model construction
Miller-Jensen K, Arnold K. Using data to guide model construction. 2018, 51-70. DOI: 10.1201/9781315119847-4.Peer-Reviewed Original ResearchPartial least squares discriminant analysisEffective health careDisease-related changesImmune cellsImmune parametersLeast squares discriminant analysisSquares discriminant analysisDisease statesHealth careImmunology researchIndividual immune parametersTissue phenotypeAccurate assessmentNovel biological insightsAdvancing systems immunology through data-driven statistical analysis
Fong LE, Muñoz-Rojas AR, Miller-Jensen K. Advancing systems immunology through data-driven statistical analysis. Current Opinion In Biotechnology 2018, 52: 109-115. PMID: 29656236, PMCID: PMC6294467, DOI: 10.1016/j.copbio.2018.03.009.Peer-Reviewed Original ResearchMyeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity
Perry CJ, Muñoz-Rojas AR, Meeth KM, Kellman LN, Amezquita RA, Thakral D, Du VY, Wang JX, Damsky W, Kuhlmann AL, Sher JW, Bosenberg M, Miller-Jensen K, Kaech SM. Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. Journal Of Experimental Medicine 2018, 215: 877-893. PMID: 29436395, PMCID: PMC5839759, DOI: 10.1084/jem.20171435.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD40 AntigensCell ProliferationImmunotherapyInflammationInterferon-gammaMacrophagesMelanoma, ExperimentalMiceMyeloid CellsNeoplasmsPhenotypeProto-Oncogene Proteins B-rafPTEN PhosphohydrolaseReceptors, Granulocyte-Macrophage Colony-Stimulating FactorRNA, MessengerSurvival AnalysisT-LymphocytesTranscription, GeneticTumor Necrosis Factor-alphaConceptsCombination therapyEffective antitumor immune responseProtective T cell responsesTumor-associated myeloid cellsM2-like stateCheckpoint inhibitor therapyAntitumor immune responseT cell responsesCSF-1R inhibitorAntitumor immunityInhibitor therapySuch patientsIL-12IL-6Cancer immunotherapyTAM subsetsUntreated tumorsT cellsImmune responseMouse modelTherapeutic targetTAM subpopulationsMyeloid cellsTumor growthCell responsesNF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise
Wong VC, Bass VL, Bullock ME, Chavali AK, Lee REC, Mothes W, Gaudet S, Miller-Jensen K. NF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise. Cell Reports 2018, 22: 585-599. PMID: 29346759, PMCID: PMC5812697, DOI: 10.1016/j.celrep.2017.12.080.Peer-Reviewed Original ResearchConceptsTranscriptional noiseIntegration sitesDiverse phenotypesRNA polymerase II regulationNoisy gene expressionGenomic integration sitesLive-cell imagingNF-κB activationChromatin environmentChromatin stateViral activationChromatin interactionsTranscript abundanceTranscription factor nuclear factor κBDivergent phenotypesGene expressionNoisy expressionNF-κBTranscript numbersNuclear factor κBPhenotypeTumor necrosis factorFactor κBActivationExpression