Meningitic Escherichia coli K1 Penetration and Neutrophil Transmigration Across the Blood–Brain Barrier are Modulated by Alpha7 Nicotinic Receptor 英文参考文献.docVIP

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Meningitic Escherichia coli K1 Penetration and Neutrophil Transmigration Across the Blood–Brain Barrier are Modulated by Alpha7 Nicotinic Receptor 英文参考文献.doc

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Meningitic Escherichia coli K1 Penetration and Neutrophil Transmigration Across the Blood–Brain Barrier are Modulated by Alpha7 Nicotinic Receptor 英文参考文献

MeningiticEscherichiacoliK1Penetrationand NeutrophilTransmigrationAcrosstheBlood–Brain BarrierareModulatedbyAlpha7NicotinicReceptor FengChi1.,LinWang1,2.,XueyeZheng1,Chun-HuaWu1,AmbroseJong1,MichaelA.Sheard1,WeiShi1, Sheng-HeHuang1* 1DepartmentofPediatrics,SabanResearchInstitute,UniversityofSouthernCalifornia,ChildrensHospitalLosAngeles,LosAngeles,California,UnitedStatesofAmerica, 2DepartmentofHistologyandEmbryology,SchoolofBasicMedicalScience,WuhanUniversity,Wuhan,China Abstract Alpha7 nicotinic acetylcholine receptor (nAChR), an essential regulator of inflammation, is abundantly expressed in hippocampalneurons,whicharevulnerabletobacterialmeningitis.However,itisunknownwhethera7nAChRcontributes totheregulationoftheseevents.Inthisreport,anaggravatingroleofa7nAChRinhostdefenseagainstmeningiticE.coli infection was demonstrated by using a7-deficient (a7-/-) mouse brain microvascular endothelial cells (BMEC) and animal modelsystems.Asshowninourinvitroandinvivostudies,E.coliK1invasionandpolymorphonuclearneutrophil(PMN) transmigrationacrosstheblood-brainbarrier(BBB)weresignificantlyreducedina7-/-BMECanda7-/-mice.Stimulationby nicotine was abolished in the a7-/- cells and animals. The same blocking effect was achieved by methyllycaconitine (a7 antagonist).ThetightjunctionmoleculesoccludinandZO-1weresignificantlyreducedinthebraincortexofwildtypemice infected with E. coli and treated with nicotine, compared to a7-/- cells and animals. Decreased neuronal injury in the hippocampaldentategyruswasobservedina7-/-micewithmeningitis.Proinflammatorycytokines(IL-1b,IL-6,TNFa ,MCP-1, MIP-1alpha,andRANTES)andadhesionmolecules(CD44andICAM-1)weresignificantlyreducedinthecerebrospinalfluids ofthea7-/-micewithE.colimeningitis.Furthermore,a7nAChRisthemajorcalciumchannelfornicotine-andE.coliK1- increased intracellular calcium concentrations of mouse BMEC. Taken together, our data suggest that a7 nAChR plays a detrimentalroleinthehostdefenseagainstmeningiticinfectionbymodulationofpathogenin