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 neurotoxicity LPS-induced microglial activation, proinflammatory cytokines in hippocampus, and neuroinflammation-associated cognitive deficits also decreased as a result of intracerebroventricular injection of recombinant ORM2 protein Moreover, 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. 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.

Systemic inflammation impairs microglial Aβ clearance through NLRP 3 inflammasome

“…This phenomenon was characterized by a 50% reduction in the number of branches, bifurcations, path length, and maximum branch order. Together, these changes indicate a substantial loss of surveillance capacity in line with similar findings by previous immunohistochemical studies (Qin et al , ; Gyoneva et al , ; Jo et al , ). Since microglia may undergo age‐dependent changes affecting their reaction to external stimuli, mice were studied at 5 (adult) and 15 months (aged) of age.…”

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

“…The intercellular cross‐talk in the diseased brain may include microglia‐dependent activation of astrocytes (Liddelow et al, ) as well as astrocyte‐dependent recruitment or activation of microglia (Jo et al, ; Skripuletz et al, ). Indeed, both microgliosis and astrogliosis occur in various SPG/PMD patients and mouse models (overview in Marteyn & Baron‐Van Evercooren, ) including the Plp null/Y mouse model of SPG2 (de Monasterio‐Schrader et al, ).…”

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…Importantly, next to instructive functions of microglia towards astrocytes, astrocytes can direct microglial functioning as well. Astrocyte‐derived factors regulate microglial activation (M. Jo et al, ; Norden, Fenn, Dugan, & Godbout, ; Rocha, Cristovão, Campos, Fonseca, & Baltazar, ), phagocytosis (Jeon et al, ), and promote microglial synapse engulfment (Vainchtein et al, ). Astrocytes also actively phagocytose synapses themselves (Chung et al, ).…”