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

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.

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis

“…SPP1 is an inflammatory cytokine that is elevated in the brains of those with HIVE, as well as in the cerebrospinal fluid of HIV-infected individuals irrespective of CNS disease [ 67 ]. Its production is thought to help limit neuroinflammation during HIV infection [ 68 ].…”

“…SPP1 is an inflammatory cytokine that is elevated in the brains of those with HIVE, as well as in the cerebrospinal fluid of HIV-infected individuals irrespective of CNS disease [67]. Its production is thought to help limit neuroinflammation during HIV infection [68]. We next examined genes encoding proteins that affect cellular signaling and its regulation, as well as transcription factors (Figure 7, genes shown in the figure are indicated in bold in the text.)…”

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

“…Following publication of the original article [ 1 ], the authors noticed that there are several images for Fig. 2 that are missing from the published article.…”

Sex-stratified single-cell RNA-Seq analysis identifies sex-specific and cell type-specific transcriptional responses in Alzheimer’s disease across two brain regions.

“…2a), which is consistent with previous bulk tissue analysis 34 . Some of the differentially expressed genes include LINGO1, a negative regulator of myelination 38,39 , which we found upregulated in all AD compared to control female cell types; SLC1A3, which encodes excitatory amino acid transporter 1 that transports glutamate in the synaptic cleft 40 and was perturbed in all female AD compared to control cell types except oligodendrocytes and OPCs; and SPP1, a protein involved in neuroinflammation also known as Osteopontin 41 that we observed to be upregulated in AD versus control samples of both female and male excitatory neurons and microglia, as well as female astrocytes and inhibitory neurons. Also, clustering samples by AD compared to control pseudo-bulk cell type gene expression (Fig.…”

“…Within each cell type, we observed DEGs, a number of which are relevant to and have been studied in AD (e.g. NRXN1 42 , SPP1 41 , DHFR 43 , SGK1 44 , ERBB2IP 45 ), meeting significance and LFC thresholds. These DEGs are shared by both sexes in AD versus control astrocytes, microglia, and excitatory neurons, with consistent directionality in both sexes (Fig.…”