Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection

Journal of Neuroinflammation

Kelly A. Metcalf Pate¹  Bess Carlson¹  Claire Lyons¹  Amanda M. Brown²  Farina J. Mahmud³  Maria Chacona³  Thomas Boucher³  Elizabeth Greif³  Martin G. Pomper⁴  Polina Sysa-Shah⁴  William B. Mathews⁴  Yong Du⁴  Robert F. Dannals⁴ 

[1] Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine;Department of Neurology and Neuroscience;Department of Neurology, Johns Hopkins University School of Medicine;Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine;

关键词: Neuroimaging;    Neuroinflammation;    Microglial activation;    DPA-713;    Purkinje cells;    Human immunodeficiency virus type-1;   

DOI  :  10.1186/s12974-020-01949-4

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown