2023
Trained immunity induced by high‐salt diet impedes stroke recovery
Lin T, Jiang D, Chen W, Lin J, Zhang X, Chen C, Hsu C, Lai L, Chen P, Yang K, Sansing L, Chang C. Trained immunity induced by high‐salt diet impedes stroke recovery. EMBO Reports 2023, 24: e57164. PMID: 37965920, PMCID: PMC10702837, DOI: 10.15252/embr.202357164.Peer-Reviewed Original ResearchConceptsInnate immune memoryMonocyte-derived macrophagesStroke recoveryInflammatory responseBone marrowImmune memoryHigh-salt dietCause of morbidityInitial inflammatory responsePotential therapeutic targetLoss of Nr4a1Stroke outcomeStroke brainIntracerebral hemorrhageBrain recoverySterile inflammationHealthy miceTissue injurySevere formTherapeutic targetAlternative activationImmune primingReparative functionsProgenitor cellsNR4A familyEmbracing Heterogeneity in The Multicenter Stroke Preclinical Assessment Network (SPAN) Trial
Morais A, Locascio J, Sansing L, Lamb J, Nagarkatti K, Imai T, van Leyen K, Aronowski J, Koenig J, Bosetti F, Lyden P, Ayata C, Bosetti F, Koenig J, Lyden P, Lamb J, Nagarkatti K, Hess D, Kamat P, Khan M, Dhandapani K, Arbab A, Siddiqui S, Smith C, Nisar M, Leira E, Chauhan A, Dhanesha N, Patel R, Kumskova M, Thedens D, Wang K, Ayata C, Morais A, Imai T, Qin T, Jin X, Erdogan T, Yu L, Mandeville J, Kimberly W, Whittier J, Lo E, Arai K, Van Leyen K, Sansing L, Hyder F, Mihailovic J, Sanganahalli B, Diaz-Perez S, Velazquez S, Beatty H, Johnson C, Herman A, Boisserand L, Immakavar E, Koehler R, Dawson T, Dawson V, Shi Y, Avery B, Lannon S, Bibic A, Akhter K, Karuppagounder S, Aronowski J, McCullough L, Obertas L, Goh A, Huang S, Chauhan A. Embracing Heterogeneity in The Multicenter Stroke Preclinical Assessment Network (SPAN) Trial. Stroke 2023, 54: 620-631. PMID: 36601951, PMCID: PMC9870939, DOI: 10.1161/strokeaha.122.040638.Peer-Reviewed Original ResearchConceptsTotal anesthesia durationAnesthesia durationIndependent predictorsMultivariable analysisClinical trialsTransient focal cerebral ischemiaFocal cerebral ischemiaCerebral blood flowLaser Doppler flowCentralized randomizationModified intentionTreat populationExperimental strokeCerebral ischemiaDoppler flowRodent modelsMCAOBlood flowNetwork trialFlow dropPreclinical trialsMouse cohortsStudy designTrialsTrial onset
2022
The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results
Lyden PD, Bosetti F, Diniz MA, Rogatko A, Koenig JI, Lamb J, Nagarkatti KA, Cabeen RP, Hess DC, Kamat PK, Khan MB, Wood K, Dhandapani K, Arbab AS, Leira EC, Chauhan AK, Dhanesha N, Patel RB, Kumskova M, Thedens D, Morais A, Imai T, Qin T, Ayata C, Boisserand LSB, Herman AL, Beatty HE, Velazquez SE, Diaz-Perez S, Sanganahalli BG, Mihailovic JM, Hyder F, Sansing LH, Koehler RC, Lannon S, Shi Y, Karuppagounder SS, Bibic A, Akhter K, Aronowski J, McCullough LD, Chauhan A, Goh A, Siddiqui S, Sheth K, Matouk C, Cruz C, Zhou J, Dawson V, Dawson T, Liang J, van Zijl P, Zeiler S, Taylor Kimberly W, Erdogan T, Yu L, Mandeville J, Whittier J. The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results. Stroke 2022, 53: 1802-1812. PMID: 35354299, PMCID: PMC9038686, DOI: 10.1161/strokeaha.121.038047.Peer-Reviewed Original ResearchConceptsPreclinical assessmentStroke treatmentCandidate treatmentMiddle cerebral artery occlusion (MCAO) surgeryClinical stroke trialsSuccessful stroke treatmentInclusion/exclusion criteriaStroke clinical trialsClinical trial designYoung male animalsComorbid diseasesOcclusion surgeryCerebral ischemiaNeurological disabilityComorbid conditionsStroke trialsProtocol adherenceBlinded assessmentSuch therapyClinical trialsClinical studiesExclusion criteriaTrial designAged animalsOutcome assessment
2021
International Post Stroke Epilepsy Research Consortium (IPSERC): A consortium to accelerate discoveries in preventing epileptogenesis after stroke
Mishra NK, Engel J, Liebeskind DS, Sharma VK, Hirsch LJ, Kasner SE, French JA, Devinsky O, Friedman A, Dawson J, Quinn TJ, Selim M, de Havenon A, Yasuda CL, Cendes F, Benninger F, Zaveri HP, Burneo JG, Srivastava P, Singh M, Bhatia R, Vishnu VY, Bentes C, Ferro J, Weiss S, Sivaraju A, Kim JA, Galovic M, Gilmore EJ, Pitkänen A, Davis K, Sansing LH, Sheth KN, Paz JT, Singh A, Sheth S, Worrall BB, Grotta JC, Casillas-Espinos PM, Chen Z, Nicolo JP, Yan B, Kwan P, Consortium F. International Post Stroke Epilepsy Research Consortium (IPSERC): A consortium to accelerate discoveries in preventing epileptogenesis after stroke. Epilepsy & Behavior 2021, 127: 108502. PMID: 34968775, DOI: 10.1016/j.yebeh.2021.108502.Peer-Reviewed Original ResearchExogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice
McCullough LD, Roy-O’Reilly M, Lai YJ, Patrizz A, Xu Y, Lee J, Holmes A, Kraushaar DC, Chauhan A, Sansing LH, Stonestreet BS, Zhu L, Kofler J, Lim YP, Venna VR. Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice. Journal Of Clinical Investigation 2021, 131: e144898. PMID: 34580244, PMCID: PMC8409590, DOI: 10.1172/jci144898.Peer-Reviewed Original ResearchConceptsInter-α inhibitor proteinsIschemic strokeStroke outcomeStroke modelComplement activationBeneficial effectsMultiple stroke modelsNeutralization of histonesPost-stroke administrationIschemic stroke outcomeExperimental ischemic strokeIschemic stroke patientsExperimental stroke modelsModel of sepsisPotential therapeutic candidateExcess complement activationIaIp levelsStroke onsetStroke patientsProinflammatory cytokinesAged miceExtracellular histonesClinical relevanceTherapeutic candidateTherapeutic efficacyDivergent Functions of Tissue-Resident and Blood-Derived Macrophages in the Hemorrhagic Brain
Chang CF, Goods BA, Askenase MH, Beatty HE, Osherov A, DeLong JH, Hammond MD, Massey J, Landreneau M, Love JC, Sansing LH. Divergent Functions of Tissue-Resident and Blood-Derived Macrophages in the Hemorrhagic Brain. Stroke 2021, 52: 1798-1808. PMID: 33840225, PMCID: PMC8085165, DOI: 10.1161/strokeaha.120.032196.Peer-Reviewed Original ResearchConceptsMonocyte-derived macrophagesIntracerebral hemorrhageT cell proliferationCore transcriptional programDifferential gene expressionDistinct transcriptional signaturesBone marrow-derived macrophagesAntigen-specific T cell proliferationTranscriptional programsCD4 T cell proliferationLongitudinal transcriptomic analysisVivo phagocytosis assaysTranscriptomic analysisDivergent functionsMarrow-derived macrophagesMHCII genesTissue-resident microgliaAntigen-presenting capabilityAutologous blood injectionGene expressionPrimary microglia culturesInnate immune cellsPhagocytosis of debrisTranscriptional signatureBlood-derived macrophagesEndothelial cell secreted VEGF-C enhances NSC VEGFR3 expression and promotes NSC survival
Matta R, Feng Y, Sansing LH, Gonzalez AL. Endothelial cell secreted VEGF-C enhances NSC VEGFR3 expression and promotes NSC survival. Stem Cell Research 2021, 53: 102318. PMID: 33836422, PMCID: PMC8243729, DOI: 10.1016/j.scr.2021.102318.Peer-Reviewed Original Research
2020
Depletion of CD4 T cells provides therapeutic benefits in aged mice after ischemic stroke
Harris NM, Roy-O'Reilly M, Ritzel RM, Holmes A, Sansing LH, O'Keefe LM, McCullough LD, Chauhan A. Depletion of CD4 T cells provides therapeutic benefits in aged mice after ischemic stroke. Experimental Neurology 2020, 326: 113202. PMID: 31954116, PMCID: PMC7059209, DOI: 10.1016/j.expneurol.2020.113202.Peer-Reviewed Original ResearchConceptsIP-10 levelsMiddle cerebral artery occlusionCD4 T cellsT cellsIschemic strokeStroke patientsIsotype controlBrain-infiltrating T cellsCD4 T-cell depletionCerebral artery occlusionT-cell depletionAged mouse modelAged male micePro-inflammatory factorsT cell dysfunctionPro-inflammatory cytokinesAnti-CD4 antibodiesAged stroke patientsIgG isotype controlCD4 treatmentDepletion antibodyArtery occlusionExperimental strokeStroke onsetSham surgeryAging exacerbates neutrophil pathogenicity in ischemic stroke
Roy-O'Reilly MA, Ahnstedt H, Spychala MS, Munshi Y, Aronowski J, Sansing LH, McCullough LD. Aging exacerbates neutrophil pathogenicity in ischemic stroke. Aging 2020, 12: 436-461. PMID: 31927534, PMCID: PMC6977697, DOI: 10.18632/aging.102632.Peer-Reviewed Original ResearchConceptsIschemic stroke patientsIschemic strokeNeutrophil-activating cytokineStroke patientsNeutrophil functionNeutrophil reactive oxygen speciesPoor post-stroke outcomesDepletion of neutrophilsPro-inflammatory functionsStrong risk factorExperimental mouse modelPost-stroke outcomesHigher stroke mortalityStroke outcomePoor outcomeFunctional outcomeStroke mortalityLong-term benefitsRisk factorsSpecific monoclonal antibodiesNeutrophil trafficTissue injuryYoung miceAged subjectsMouse model
2019
Bexarotene Enhances Macrophage Erythrophagocytosis and Hematoma Clearance in Experimental Intracerebral Hemorrhage
Chang CF, Massey J, Osherov A, Angenendt da Costa LH, Sansing LH. Bexarotene Enhances Macrophage Erythrophagocytosis and Hematoma Clearance in Experimental Intracerebral Hemorrhage. Stroke 2019, 51: 612-618. PMID: 31826730, PMCID: PMC7135897, DOI: 10.1161/strokeaha.119.027037.Peer-Reviewed Original ResearchConceptsIntracerebral hemorrhageBexarotene treatmentFunctional recoveryHematoma clearanceRetinoid X receptor agonistExperimental intracerebral hemorrhageX receptor agonistMacrophage TNF productionMarrow-derived macrophagesNeurological recoveryNeurobehavioral recoveryNeurological deficitsAutologous bloodBrain recoveryHematoma volumeReceptor agonistTherapeutic effectMacrophage expressionTNF productionMouse modelVivo phagocytosisMacrophage phenotypeFlow cytometryHistological analysisErythrocyte metabolitesTransforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke
Howe MD, Furr JW, Munshi Y, Roy-O’Reilly M, Maniskas ME, Koellhoffer EC, d’Aigle J, Sansing LH, McCullough LD, Urayama A. Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke. GeroScience 2019, 41: 543-559. PMID: 31721012, PMCID: PMC6885082, DOI: 10.1007/s11357-019-00118-7.Peer-Reviewed Original ResearchConceptsPoor functional recoveryFunctional recoveryExperimental strokeAstrocyte activationStroke patientsAged brainCultured astrocytesSerum TGF-β levelsTGF-β receptor inhibitionPotential new treatment strategyGlial scar developmentElderly stroke patientsTGF-β levelsPoor functional outcomeOxygen-glucose deprivationCerebrospinal fluid distributionNew treatment strategiesPrimary cultured astrocytesExogenous TGF-β stimulationBasement membraneTGF-β stimulationNeurological recoveryElderly patientsSerum levelsFunctional outcome