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 central nervous system. 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 pro-inflammatory mediators and reduced microglia-mediated neurotoxicity in vitro. LPS-induced microglial activation, pro-inflammatory cytokines in hippocampus, and neuroinflammation-associated cognitive deficits also decreased as a result of intracerebroventricular injection of recombinant ORM2 protein in vivo. Moreover, lentiviral shRNA-mediated Orm2 knockdown enhanced LPS-induced pro-inflammatory 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. Taken 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 therapeutically exploited for the treatment of neuroinflammatory diseases.
Neural 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.
The authors declare no competing financial interests.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2016M3C7A1904148, 2015R1A2A1A10051958). This study was also supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C3331).