title: Astrocytic Orosomucoid-2 Modulates Microglial Activation and Neuroinflammation.
abstract: Orosomucoid (ORM) is an acute-phase protein that belongs to the immunocalin subfamily, a group of small-molecule-binding proteins 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 induced in the mouse brain after systemic injection of lipopolysaccharide (LPS). Plasma levels of ORM2 were also significantly higher in 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 neurotoxicityin vitroLPS-induced microglial activation, proinflammatory cytokines in hippocampus, and neuroinflammation-associated cognitive deficits also decreased as a result of intracerebroventricular injection of recombinant ORM2 proteinin vivoMoreover, lentiviral shRNA-mediated Orm2 knockdown enhanced LPS-induced proinflammatory cytokine gene expression and microglial activation in the hippocampus. Mechanistically, ORM2 inhibited C-C chemokine ligand 4 (CCL4)-induced microglial migration and activation by blocking the interaction of CCL4 with C-C chemokine receptor type 5. Together, the results from our cultured glial cells, mouse neuroinflammation model, and patient studies suggest that ORM2 is a novel mediator of astrocyte-microglial interaction. We also report that ORM2 exerts anti-inflammatory effects by modulating microglial activation and migration during brain inflammation. ORM2 can be exploited therapeutically for the treatment of neuroinflammatory diseases.SIGNIFICANCE STATEMENTNeural cell interactions are important for brain physiology and pathology. Particularly, the interaction between non-neuronal cells plays a central role in regulating brain inflammation, which is closely linked to many brain disorders. Here, we newly identified orosomucoid-2 (ORM2) as an endogenous protein that mediates such non-neuronal glial cell interactions. Based on the critical role of astrocyte-derived ORM2 in modulating microglia-mediated neuroinflammation, ORM2 can be exploited for the diagnosis, prevention, or treatment of devastating brain disorders that have a strong neuroinflammatory component, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, Biomedical Convergence Program for Creative Talent, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea, and.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Jo
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, Biomedical Convergence Program for Creative Talent, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea, and.
authors.forename: Jong-Heon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, Biomedical Convergence Program for Creative Talent, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea, and.
authors.forename: Gyun Jee
authors.initials: GJ
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, Biomedical Convergence Program for Creative Talent, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea, and.
authors.forename: Minchul
authors.initials: M
authors.lastname: Seo
authors.affiliation: Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
authors.forename: Eun Mi
authors.identifier: 0000-0002-3130-8572
authors.initials: EM
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, Biomedical Convergence Program for Creative Talent, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea, and ksuk@knu.ac.kr.
authors.forename: Kyoungho
authors.identifier: 0000-0002-9555-4203
authors.initials: K
authors.lastname: Suk
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000276:immunology; D004660:Encephalitis / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009961:Orosomucoid / Q000276:immunology*
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; C573095:ORM2 protein, human; D009961:Orosomucoid
keywords: CCR5; Orm2; astrocyte; microglia; migration; neuroinflammation