Technical Advance: Inhibition of neutrophil chemotaxis by colchicine is modulated through viscoelastic properties of subcellular compartments

[摘要] Colchicineisanefficientdrugforthemanagementofinflammatorydiseases,suchasgoutyarthritisandfamilialMediterraneanfever.Itaffectsneutrophilactivitybyinterferingwiththeformationofmicrotubules.Totestthehypothesisthattherapeuticconcentrationsofcolchicinemodulatethemechanicalpropertiesofthesecells,weappliedacombinationofbiophysicaltechniques(opticalstretchingandmicrorheology)toanalyzecellulardeformability.Thecontributionofthesubcellularcompartmentstotheregulationofcellmechanicswasdeterminedbyfittingamulticomponentmodelofcellularviscoelasticitytotime‐dependentdeformationcurves.Neutrophilswerefoundtobelessdeformableinresponseto10ng/mlcolchicine.Themodel‐basedanalysisofcellulardeformationrevealedadecreaseincytoplasmaticelasticityandasubstantialincreaseinbothelasticityandviscosityofthecellmembranecompartmentinresponsetocolchicine.Theseresultscorrelatewithareducednumberofcytoplasmaticmicrotubulesandanincreaseinsubcorticalactinfilaments.Thelatterfindingwasconfirmedbymicrorheologyandfluorescencemicroscopy.Neutrophilmigrationthroughsmallporesrequiringsubstantialcellulardeformations,butnotthroughlargepores,wassignificantlyimpairedbycolchicine.Thesedatademonstratethatcolchicinedeterminesmechanicsofneutrophilsand,thereby,motilityinconfinedspaces,whichiscrucialduringextravasationofneutrophilsinresponsetoinflammatorystimuli...

[学科分类] 生理学

[关键词] cellular deformability;cytoskeleton;extravasation;inflammation