Featured Publications
Tissue-specific modifier alleles determine Mertk loss-of-function traits
Akalu YT, Mercau ME, Ansems M, Hughes LD, Nevin J, Alberto EJ, Liu XN, He LZ, Alvarado D, Keler T, Kong Y, Philbrick WM, Bosenberg M, Finnemann SC, Iavarone A, Lasorella A, Rothlin CV, Ghosh S. Tissue-specific modifier alleles determine Mertk loss-of-function traits. ELife 2022, 11: e80530. PMID: 35969037, PMCID: PMC9433089, DOI: 10.7554/elife.80530.Peer-Reviewed Original ResearchConceptsAnti-tumor immunityKO miceRetinal pigment epitheliumRetinal degenerationPigment epitheliumPro-inflammatory tumor microenvironmentSyngeneic mouse tumor modelsKO mice displayEarly-onset retinal degenerationSevere retinal degenerationMouse tumor modelsFailure of macrophagesKnockout mouse modelPhotoreceptor outer segmentsMouse modelMice displayTumor modelTumor microenvironmentMacrophage phagocytosisReceptor tyrosine kinasesMiceCritical roleDegenerationMerTKImmunityInflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in Mertk-associated retinitis pigmentosa
Mercau M, Akalu Y, Mazzoni F, Gyimesi G, Alberto E, Kong Y, Hafler B, Finnemann S, Rothlin C, Ghosh S. Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in Mertk-associated retinitis pigmentosa. Science Advances 2023, 9: eade9459. PMID: 36662852, PMCID: PMC9858494, DOI: 10.1126/sciadv.ade9459.Peer-Reviewed Original ResearchConceptsRetinal pigment epitheliumEarly-onset photoreceptor degenerationPR degenerationPigment epitheliumPhotoreceptor degenerationMERTK-associated retinitis pigmentosaJAK1/2 inhibitor ruxolitinibMicroglia activationMonocyte infiltrationInhibitor ruxolitinibMouse modelInflammationLoss of functionDefective phagocytosisInflammation drivesRetinitis pigmentosaDegenerationHypomorphic expressionMiceEpitheliumPhagocytosisRuxolitinibPigmentosaSeverity
2024
Feeding the wrath with myelin
Ghosh S, Rothlin C. Feeding the wrath with myelin. Trends In Immunology 2024, 45: 729-731. PMID: 39341708, DOI: 10.1016/j.it.2024.09.004.Peer-Reviewed Original Research
2023
Age-dependent differences in efferocytosis determine the outcome of opsonophagocytic protection from invasive pathogens
Bee G, Lokken-Toyli K, Yeung S, Rodriguez L, Zangari T, Anderson E, Ghosh S, Rothlin C, Brodin P, Khanna K, Weiser J. Age-dependent differences in efferocytosis determine the outcome of opsonophagocytic protection from invasive pathogens. Immunity 2023, 56: 1255-1268.e5. PMID: 37059107, PMCID: PMC10330046, DOI: 10.1016/j.immuni.2023.03.018.Peer-Reviewed Original ResearchConceptsAge-dependent differencesNeonatal neutrophilsEarly lifeModulation of CD11bCD11b surface expressionAge-dependent susceptibilitySpn infectionPeripheral bloodMore CD11bMouse modelInfection outcomesStreptococcus pneumoniaeNeutrophilsCD11bEfferocytosisSystemic expressionSurface expressionNeonatesOpsonophagocytosisInvasive pathogensOutcomesPopulation levelCD169PathogensExpression
2022
Regulation of bone homeostasis by MERTK and TYRO3
Engelmann J, Zarrer J, Gensch V, Riecken K, Berenbrok N, Luu T, Beitzen-Heineke A, Vargas-Delgado M, Pantel K, Bokemeyer C, Bhamidipati S, Darwish I, Masuda E, Burstyn-Cohen T, Alberto E, Ghosh S, Rothlin C, Hesse E, Taipaleenmäki H, Ben-Batalla I, Loges S. Regulation of bone homeostasis by MERTK and TYRO3. Nature Communications 2022, 13: 7689. PMID: 36509738, PMCID: PMC9744875, DOI: 10.1038/s41467-022-33938-x.Peer-Reviewed Original ResearchConceptsCancer-induced bone lossBone homeostasisBone lossBone-resorbing osteoclastsBone metastasesProlong survivalOsteoanabolic therapyMultiple myelomaLung cancerBone-forming osteoblastsBone massHealthy micePreclinical modelsOsteoblast numberMerTKTyro3Bone formationMicePotent regulatorCell type-specific functionsFine equilibriumBlockadeCancerHomeostasisOsteoblast differentiation
2019
Funerals and Feasts: The Immunological Rites of Cell Death.
Galimberti VE, Rothlin CV, Ghosh S. Funerals and Feasts: The Immunological Rites of Cell Death. The Yale Journal Of Biology And Medicine 2019, 92: 663-674. PMID: 31866781, PMCID: PMC6913811.BooksConceptsReceptor tyrosine kinasesCell deathMolecular mechanismsCell death modalitiesUnscheduled cell deathNon-self recognitionImportant negative regulatorDead cellsMulticellular organismsAdult organismDeath modalitiesProper immune responseNegative regulatorTyrosine kinaseMolecular processesInjury/infectionImmune responseMolecular modalitiesOmnipresent processOrganismsDefective developmentMost tissuesImmune system functionTAM familyFibrosis/scarringCracking the Cell Death Code
Rothlin CV, Ghosh S. Cracking the Cell Death Code. Cold Spring Harbor Perspectives In Biology 2019, 12: a036343. PMID: 31548182, PMCID: PMC7197433, DOI: 10.1101/cshperspect.a036343.Peer-Reviewed Original Research
2018
Coagulopathies and inflammatory diseases: ‘…glimpse of a Snark’
del Carmen S, Hapak SM, Ghosh S, Rothlin CV. Coagulopathies and inflammatory diseases: ‘…glimpse of a Snark’. Current Opinion In Immunology 2018, 55: 44-53. PMID: 30268838, PMCID: PMC6366937, DOI: 10.1016/j.coi.2018.09.005.BooksConceptsAnti-pathogen defenseUnderlying molecular basisInflammatory diseasesMolecular basisSelective pressureHost defense mechanismsSubset of patientsDefense mechanismsVertebratesRegulation of inflammationHuman populationThrombophilic stateTherapeutic roleDefenseDiseaseInvertebratesCoagulopathyInflammationPhysical injuryMutationsRegulationPathogensCascadeApixabanThrombophiliaAxon Regeneration: Antagonistic Signaling Pairs in Neuronal Polarization
Hapak SM, Ghosh S, Rothlin CV. Axon Regeneration: Antagonistic Signaling Pairs in Neuronal Polarization. Trends In Molecular Medicine 2018, 24: 615-629. PMID: 29934283, DOI: 10.1016/j.molmed.2018.05.007.BooksPAR3–PAR6–atypical PKC polarity complex proteins in neuronal polarization
Hapak SM, Rothlin CV, Ghosh S. PAR3–PAR6–atypical PKC polarity complex proteins in neuronal polarization. Cellular And Molecular Life Sciences 2018, 75: 2735-2761. PMID: 29696344, PMCID: PMC11105418, DOI: 10.1007/s00018-018-2828-6.BooksConceptsPar3-Par6Neuronal polarityNeuronal polarizationPolarity complex proteinsAPKC kinase activityEukaryotic cell typesProtein complexesComplex proteinsKinase activityPar6APKCSignaling mechanismCell typesPar3Effector moleculesProteinImportant roleEffector functionsPolarityComplexesFundamental featuresPathwayRoleAssemblyCellsaPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1
Chibly AM, Wong WY, Pier M, Cheng H, Mu Y, Chen J, Ghosh S, Limesand KH. aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1. Scientific Reports 2018, 8: 6347. PMID: 29679075, PMCID: PMC5910385, DOI: 10.1038/s41598-018-24678-4.Peer-Reviewed Original Research
2017
Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage
Chang CF, Goods BA, Askenase MH, Hammond MD, Renfroe SC, Steinschneider AF, Landreneau MJ, Ai Y, Beatty HE, da Costa LHA, Mack M, Sheth KN, Greer DM, Huttner A, Coman D, Hyder F, Ghosh S, Rothlin CV, Love JC, Sansing LH. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. Journal Of Clinical Investigation 2017, 128: 607-624. PMID: 29251628, PMCID: PMC5785262, DOI: 10.1172/jci95612.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisAxl Receptor Tyrosine KinaseBrain InjuriesCerebral HemorrhageC-Mer Tyrosine KinaseErythrocytesHematomaHumansImmunity, InnateInflammationMacrophagesMaleMiceMice, Inbred C57BLMice, TransgenicPhagocytosisPhenotypeProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSolubilityTreatment OutcomeConceptsMonocyte-derived macrophagesIntracerebral hemorrhageEryptotic erythrocytesNeurological recoveryHematoma clearanceExperimental intracerebral hemorrhageReceptor tyrosine kinase AXLHuman monocyte-derived macrophagesTyrosine kinase AXLICH onsetFunctional outcomeBrain injuryTissue injurySoluble AxlDynamic phenotypic changesAlternative activationPhenotypic changesMacrophage phenotypeIron depositionMurine brainMacrophage responseRestorative functionEfferocytosisMacrophagesEngulfment of erythrocytesDeath begets a new beginning
Bosurgi L, Hughes LD, Rothlin CV, Ghosh S. Death begets a new beginning. Immunological Reviews 2017, 280: 8-25. PMID: 29027219, PMCID: PMC5658037, DOI: 10.1111/imr.12585.BooksConceptsCell deathBillions of cellsApoptotic cell deathEnvironmental cuesSpecific functionsHomeostatic conditionsTissue microenvironmentApoptotic cellsDead cellsTissue repairGrowth factorCellsPhagocytosisPerpetual featureSevere tissue injuryDeathInductionAppropriate responseMicroenvironmentPhagocytesCuesMacrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells
Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, Weinstein JS, Licona-Limon P, Schmid ET, Pelorosso F, Gagliani N, Craft JE, Flavell RA, Ghosh S, Rothlin CV. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 2017, 356: 1072-1076. PMID: 28495875, PMCID: PMC5556699, DOI: 10.1126/science.aai8132.Peer-Reviewed Original ResearchConceptsApoptotic cellsTissue repair programChemotaxis genesTissue-resident macrophagesIL-4IL-13Tissue repairPattern recognition receptorsTissue repair genesCell adhesionRepair genesGenetic ablationCytokine-dependent inductionHelminth infectionsRecognition receptorsInduction of colitisGenesBroad repertoireSoluble cytokinesMacrophage functionCellsInductionHost responseEctopic activityInterleukin-4TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy
Akalu YT, Rothlin CV, Ghosh S. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunological Reviews 2017, 276: 165-177. PMID: 28258690, PMCID: PMC5381815, DOI: 10.1111/imr.12522.BooksMeSH KeywordsAdaptive ImmunityAnimalsAntibodies, MonoclonalAxl Receptor Tyrosine KinaseC-Mer Tyrosine KinaseCostimulatory and Inhibitory T-Cell ReceptorsDrug Therapy, CombinationHumansImmunity, InnateImmunotherapyNeoplasmsProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSignal TransductionTumor EscapeConceptsCheckpoint blockadeAdaptive anti-tumor immune responsesT cell checkpoint blockadeT-cell checkpoint inhibitorsAnti-tumor immune responseInnate immune cell functionDendritic cell activityInnate immune checkpointImmune checkpoint blockadeSubset of patientsInnate immune cellsAnti-tumoral immunityProduction of chemokinesImmune cell functionMode of treatmentTAM receptor tyrosine kinasesTremendous clinical successCheckpoint inhibitorsImmune checkpointsCancer immunotherapyUnresponsive patientsImmune cellsT cellsImmune responseAdaptive immunityNegative Regulation of Type 2 Immunity
de Kouchkovsky DA, Ghosh S, Rothlin CV. Negative Regulation of Type 2 Immunity. Trends In Immunology 2017, 38: 154-167. PMID: 28082101, PMCID: PMC5510550, DOI: 10.1016/j.it.2016.12.002.BooksConceptsType 2 immunityProtective host responseType 2 responsesAllergic rhinitisAtopic diseasesAtopic dermatitisMillions of individualsHost responseImmune systemImmunityInappropriate activationNegative regulationEnvironmental substancesParasitic helminthsIndustrialized worldHelminthsRhinitisImmunopathologyKey playersAsthmaDermatitisAllergensDiseaseIndividuals
2016
The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity
Chan PY, Carrera Silva EA, De Kouchkovsky D, Joannas LD, Hao L, Hu D, Huntsman S, Eng C, Licona-Limón P, Weinstein JS, Herbert DR, Craft JE, Flavell RA, Repetto S, Correale J, Burchard EG, Torgerson DG, Ghosh S, Rothlin CV. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 2016, 352: 99-103. PMID: 27034374, PMCID: PMC4935984, DOI: 10.1126/science.aaf1358.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAnimalsAsthmaBlood ProteinsDendritic CellsDisease Models, AnimalGene Knockout TechniquesHost-Parasite InteractionsHumansImmunity, InnateInterleukin-4MiceMice, Inbred C57BLMice, KnockoutNippostrongylusProtein SPyroglyphidaeReceptor Protein-Tyrosine KinasesStrongylida InfectionsT-LymphocytesConceptsType 2 immunityType 2 responsesType 2 cytokinesHuman dendritic cellsInnate immune cellsDendritic cellsAllergic diseasesImmune cellsT cellsAdaptive immunityInterleukin-4Host responseFunctional neutralizationGenetic ablationReceptor tyrosine kinasesImmunityProtective functionTyro3Tyrosine kinaseNegative regulatorPROS1CellsResponseCytokinesDisease
2015
Endosomal regulation of contact inhibition through the AMOT:YAP pathway
Cox CM, Mandell EK, Stewart L, Lu R, Johnson DL, McCarter SD, Tavares A, Runyan R, Ghosh S, Wilson JM. Endosomal regulation of contact inhibition through the AMOT:YAP pathway. Molecular Biology Of The Cell 2015, 26: 2673-2684. PMID: 25995376, PMCID: PMC4501364, DOI: 10.1091/mbc.e15-04-0224.Peer-Reviewed Original ResearchConceptsEndosomal membranesYAP activitySubconfluent cellsOrgan growth controlTranscription coactivator YesPhosphorylation-dependent regulationIntegral membrane proteinsConfluent cellsAmot proteinsEndosomal regulationContact-mediated inhibitionCytoplasmic domainEndotubinMembrane proteinsOvergrowth phenotypeInduces translocationAngiomotinYAP interactionDirect bindingGrowth controlContact inhibitionFamily membersCell growthYAPYAP pathwayPKCι interacts with Rab14 and modulates epithelial barrier function through regulation of claudin-2 levels
Lu R, Dalgalan D, Mandell EK, Parker SS, Ghosh S, Wilson JM. PKCι interacts with Rab14 and modulates epithelial barrier function through regulation of claudin-2 levels. Molecular Biology Of The Cell 2015, 26: 1523-1531. PMID: 25694446, PMCID: PMC4395131, DOI: 10.1091/mbc.e14-12-1613.Peer-Reviewed Original ResearchConceptsClaudin-2 levelsSmall GTPase Rab14Claudin-2 protein levelsClaudin-2Junction proteinsTransepithelial resistanceEpithelial polarityIntracellular punctaTight junction componentsTight junction proteinsPlasma membraneNormal assemblyRab14 expressionRab14Junction componentsPKCιKnockdownEpithelial barrier functionProtein levelsTight junctionsZO-1ProteinParacellular permeabilityClaudin-1APKCTAM Receptor Signaling in Immune Homeostasis
Rothlin CV, Carrera-Silva EA, Bosurgi L, Ghosh S. TAM Receptor Signaling in Immune Homeostasis. Annual Review Of Immunology 2015, 33: 1-37. PMID: 25594431, PMCID: PMC4491918, DOI: 10.1146/annurev-immunol-032414-112103.BooksConceptsImmune homeostasisTAM receptor signalingFunction of TAMsResolution of inflammationInnate immune responseTAM receptor tyrosine kinasesImmune settingsAutoimmune diseasesImmune responseInfectious diseasesVascular integrityReceptor tyrosine kinasesReceptor signalingDiseaseApoptotic cellsTyrosine kinaseNegative regulationRecent studiesFunctional importanceHomeostasisEssential roleInflammationCancerAxlMerTK