Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic
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(2020) 17:273
RESEARCH
Open Access
Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection Farina J. Mahmud1, Yong Du2, Elizabeth Greif1, Thomas Boucher1, Robert F. Dannals2, William B. Mathews2, Martin G. Pomper2, Polina Sysa-Shah2, Kelly A. Metcalf Pate3, Claire Lyons3, Bess Carlson3, Maria Chacona1 and Amanda M. Brown4*
Abstract Background: Osteopontin (OPN) as a secreted signaling protein is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts poorly understood. Methods: Micro-positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain is a non-invasive tool used to track neuroinflammation in living mammals. Results: In humanized, chronically HIV-infected female mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand DPA-713 was markedly upregulated in the cortex, olfactory bulb, basal forebrain, hypothalamus, and central grey matter compared to controls. Microglia immunoreactive for Iba-1 were more abundant in some HIV-infected mice, but overall, the differences were not significant between groups. TSPO+ microglia were readily detected by immunolabeling of post-mortem brain tissue and unexpectedly, two types of neurons also selectively stained positive for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase-positive neurons of the substantia nigra. Conclusions: In female mice with wild-type levels of osteopontin, increased levels of TSPO ligand uptake in the brain was seen in animals with the highest levels of persistent HIV replication. In contrast, in mice with lower levels of osteopontin, the highest levels of TSPO uptake was seen, in mice with relatively low levels of persistent infection. These findings suggest that osteopontin may act as a molecular brake regulating in the brain, the inflammatory response to HIV infection. Keywords: Neuroimaging, Neuroinflammation, Microglial activation, DPA-713, Purkinje cells, Human immunodeficiency virus type-1, Peripheral benzodiazepine receptor, Positron emission tomography, RNAscope, Ionized calcium binding adaptor molecule 1 * Correspondence: [email protected] 4 Department of Neurology and Neuroscience, Baltimore, USA Full list of author information is available at the end of the article
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