Cortical neurons are a prominent source of the proinflammatory cytokine osteopontin in HIV-associated neurocognitive disorders

Abstract

The proinflammatory cytokine osteopontin (OPN) is elevated in the cerebrospinal fluid (CSF) in individuals with HIV-associated neurocognitive disorders (HAND) and remains so in those on suppressive antiretroviral therapy. To understand the pathophysiological significance of elevated OPN in the CNS, we sought to determine the cellular source of this cytokine. As HIV-1 replicates productively in macrophages/microglia, we tested whether these cells are the predominant producers of OPN in the brain. Stringent patient selection criteria, which excluded brain tissues from those with evidence of drug abuse and dependence, were used. Uninfected normal controls, amyotrophic lateral sclerosis (ALS), HIV+ asymptomatic neurocognitive impairment (ANI), and HIV+ mild neurocognitive disorder (MND)/HIV-associated dementia (HAD) groups were included. Double-label immunohistochemistry for CNS cells and OPN was used to quantify OPN expression in astrocytes, macrophages/microglia, and neurons. While resident macrophages/microglia expressed OPN, astrocytes and unexpectedly neurons were also a major source of OPN. OPN levels in ionized Ca2+-binding adapter 1 (Iba1)/allograft inflammatory factor-1 (AIF-1)+ microglia in HIV+ ANI and MND/HAD exceeded those of HIV-negative controls and were comparable to expression seen in ALS. Moreover, in neurons, OPN was expressed at the highest levels in the HIV+ ANI group. These findings suggest that while infiltrating HIV-infected macrophages are most likely the initial source of OPN, resident CNS cells become activated and also express this inflammatory cytokine at significant levels. Moreover, as OPN levels are elevated compared to uninfected individuals and increases with the severity of impairment, it appears that the expression of OPN is persistent and sustained within the brain parenchyma in those that progress to HAND.

Spatiotemporal expression of osteopontin in the striatum of rats subjected to the mitochondrial toxin 3-nitropropionic acid correlates with microcalcification

“…These findings suggest that brain macrophages are not the only cellular source of OPN in striatal lesions. OPN has been reported to be produced by degenerating neurons in several neuropathological disorders4773747576, and by cortical neurons in HIV-associated associated neurocognitive disorders77. The presence of intracellular OPN, which lacks the vesicle-targeting signal sequence, has been reported in various types of cells including activated macrophages, osteoclasts and fibroblasts, and it has been implicated in a number of cellular processes, including migration, fusion, and motility7879808182.…”

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

“…Our prior studies implicated OPN as an upregulated protein in HIV-infected macrophages that also stimulates viral replication through a NF-κbdependent mechanism (22). We went on to demonstrate, using post-mortem brain tissue from individuals with HAND, that neurons as well as microglia, show elevated OPN expression (19). OPN knockout mice are viable and display no gross physical or behavioral abnormalities but do show disorganized wound remodeling and defective macrophage in ltration after injury or infection (42,43).…”

“…Previous in vitro, ex vivo (19) and rhesus macaque studies (20,21) have implicated a role for the multifunctional protein osteopontin (OPN) or secreted phosphoprotein-1 (SPP1) in proin ammatory signaling in HIV-associated neurocognitive disorders (HAND). Notably, the accumulating data points to several different underlying mechanisms, however the detailed mechanisms of OPN function remain to be clari ed.…”

Human endogenous retroviruses in neurologic disease

“…For HIV‐associated dementia (HAD), the incidence of the severe manifestations of HAD has dramatically decreased following the introduction of antiretroviral therapy, whereas the milder forms of HAD appear to have increased . The proposed explanations for this are varied and as yet unresolved .…”