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 ResearchMeSH KeywordsAllelesAnimalsC-Mer Tyrosine KinaseDisease Models, AnimalMiceMice, KnockoutPhagocytosisPhenotypeProto-Oncogene ProteinsRetinal DegenerationRetinal PigmentsConceptsAnti-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 ResearchMeSH KeywordsAnimalsC-Mer Tyrosine KinaseInflammationMiceProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesRetinal DegenerationRetinal Pigment EpitheliumRetinitis PigmentosaConceptsRetinal pigment epitheliumEarly-onset photoreceptor degenerationPR degenerationPigment epitheliumPhotoreceptor degenerationMERTK-associated retinitis pigmentosaJAK1/2 inhibitor ruxolitinibMicroglia activationMonocyte infiltrationInhibitor ruxolitinibMouse modelInflammationLoss of functionDefective phagocytosisInflammation drivesRetinitis pigmentosaDegenerationHypomorphic expressionMiceEpitheliumPhagocytosisRuxolitinibPigmentosaSeverity
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 ResearchMeSH KeywordsAnimalsCarrier ProteinsC-Mer Tyrosine KinaseHomeostasisMiceProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesConceptsCancer-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
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 erythrocytesThe receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer
Uribe DJ, Mandell EK, Watson A, Martinez JD, Leighton JA, Ghosh S, Rothlin CV. The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer. PLOS ONE 2017, 12: e0179979. PMID: 28727830, PMCID: PMC5519024, DOI: 10.1371/journal.pone.0179979.Peer-Reviewed Original ResearchConceptsColorectal cancerTAM receptor tyrosine kinasesReceptor tyrosine kinasesLate-stage colorectal cancerColitis-associated cancerStage colorectal cancerAnti-inflammatory effectsReceptor tyrosine kinase AXLTyro3 receptor tyrosine kinasesSufficient therapeutic benefitTyrosine kinase AXLNumber of cancersTYRO3 expressionChronic inflammationAllergic responsesTherapeutic benefitTumor cell migrationImmunological diseasesExpression associatesIndiscriminate inhibitionGene signatureAxlAxl kinase activityInflammationCancerTAM 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 immunity
2014
Tyro3, Axl, and Mertk Receptor Signaling in Inflammatory Bowel Disease and Colitis-associated Cancer
Rothlin CV, Leighton JA, Ghosh S. Tyro3, Axl, and Mertk Receptor Signaling in Inflammatory Bowel Disease and Colitis-associated Cancer. Inflammatory Bowel Diseases 2014, 20: 1472-1480. PMID: 24846720, PMCID: PMC4343000, DOI: 10.1097/mib.0000000000000050.BooksConceptsInflammatory bowel diseaseBowel diseaseImmune responseT-cell-dependent adaptive immune responsesApoptotic cellsReceptor tyrosine kinasesProinflammatory cytokine productionSuppression of inflammationAdaptive immune responsesInnate immune responseTAM receptor tyrosine kinasesPotent therapeutic opportunityDisease remissionTyrosine kinaseIntestinal inflammationCytokine productionInflammatory responseLigand Gas6Potent negative regulatorTherapeutic opportunitiesGenetic ablationInflammationProtein SReceptor signalingSuccessful management
2013
Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer
Bosurgi L, Bernink JH, Cuevas V, Gagliani N, Joannas L, Schmid ET, Booth CJ, Ghosh S, Rothlin CV. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 13091-13096. PMID: 23878224, PMCID: PMC3740859, DOI: 10.1073/pnas.1302507110.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisAxl Receptor Tyrosine KinaseAzoxymethaneC-Mer Tyrosine KinaseColitisColonColonic NeoplasmsCytokinesDextran SulfateFemaleFlow CytometryGene ExpressionMacrophagesMaleMiceMice, Inbred StrainsMice, KnockoutMucous MembraneNeutrophilsPhagocytosisProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesReverse Transcriptase Polymerase Chain ReactionSignal TransductionConceptsTumor-promoting environmentMer receptor tyrosine kinaseSystemic anticancer therapyDextran sulfate sodiumAnticancer therapyIntestinal lamina propriaAnti-inflammatory functionsInflammation-associated cancerPotential adverse effectsInflammatory signatureDendritic cellsSulfate sodiumIntestinal macrophagesProinflammatory cytokinesLamina propriaColon cancerTherapeutic targetingOncogenic roleMer inhibitorsApoptotic neutrophilsAxlMultiple cancer hallmarksReceptor tyrosine kinasesTumor cellsAdverse effects
2007
TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response
Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response. Cell 2007, 131: 1124-1136. PMID: 18083102, DOI: 10.1016/j.cell.2007.10.034.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxl Receptor Tyrosine KinaseC-Mer Tyrosine KinaseDendritic CellsGene Expression RegulationImmunity, InnateInflammationMiceMice, KnockoutOncogene ProteinsProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesReceptor, Interferon alpha-betaSignal TransductionSTAT1 Transcription FactorSuppressor of Cytokine Signaling 1 ProteinSuppressor of Cytokine Signaling 3 ProteinSuppressor of Cytokine Signaling ProteinsToll-Like ReceptorsUbiquitinationConceptsToll-like receptorsDendritic cellsImmune responseChronic inflammatory milieuInnate immune responseTAM receptor tyrosine kinasesRapid inflammatory responseType I interferon receptorCytokine-dependent activationTAM inhibitionTLR inductionInflammatory milieuInflammatory responseProinflammatory pathwaysTAM receptorsTLR signalingPleiotropic inhibitorInflammationReceptor tyrosine kinasesTranscription factor STAT1Interferon receptorEssential stimulatorReceptorsTyrosine kinaseTAM system