Astrocytic Orosomucoid-2 Modulates Microglial Activation and Neuroinflammation
- Astrocytic Orosomucoid-2 Modulates Microglial Activation and Neuroinflammation
- 황은미; Myungjin Jo; Jong-Heon Kim; Gyun Jee Song; Minchul Seo; Kyoungho Suk
- astrocyte; CCR5; microglia; migration; neuroinflammation; Orm2
- Issue Date
- Journal of neuroscience
- VOL 37, NO 11-2894
- Orosomucoid(ORM)isanacute-phaseproteinthatbelongstotheimmunocalinsubfamily,agroupofsmall-molecule-bindingproteins with immunomodulatory functions. Little is known about the role of ORM proteins in the CNS. The aim of the present study was to investigate the brain expression of ORM and its role in neuroinflammation. Expression of Orm2, but not Orm1 or Orm3, was highly inducedinthemousebrainaftersystemicinjectionoflipopolysaccharide(LPS).PlasmalevelsofORM2werealsosignificantlyhigherin patients with cognitive impairment than in normal subjects. RT-PCR, Western blot, and immunofluorescence analyses revealed that astrocytes are the major cellular sources of ORM2 in the inflamed mouse brain. Recombinant ORM2 protein treatment decreased microglial production of proinflammatory mediators and reduced microglia-mediated neurotoxicity in vitro. LPS-induced microglial activation,proinflammatorycytokinesinhippocampus,andneuroinflammation-associatedcognitivedeficitsalsodecreasedasaresult of intracerebroventricular injection of recombinant ORM2 protein in vivo. Moreover, lentiviral shRNA-mediated Orm2 knockdown enhanced LPS-induced proinflammatory cytokine gene expression and microglial activation in the hippocampus. Mechanistically, ORM2inhibitedC-Cchemokineligand4(CCL4)-inducedmicroglialmigrationandactivationbyblockingtheinteractionofCCL4with C-Cchemokinereceptortype5.Together,theresultsfromourculturedglialcells,mouseneuroinflammationmodel,andpatientstudies suggestthatORM2isanovelmediatorofastrocyte– microglialinteraction.WealsoreportthatORM2exertsanti-inflammatoryeffectsby modulatingmicroglialactivationandmigrationduringbraininflammation.ORM2canbeexploitedtherapeuticallyforthetreatmentof neuroinflammatorydiseases.
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