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

Silva K, Hope-Lucas C, White T, Hairston TK, Rameau T, Brown A - J. Neurovirol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street/Meyer 6-181, Baltimore, MD, 21287-7131, USA.

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 Ca(2+)-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.

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Double-labeled neurons expressing NeuN and OPN. See staining paradigm as given in figure legend 1. a case 16, normal; b case 25, ALS; c case 18, MND; d case 20, ANI; e case 21, MND/HAD; f case 13, HAD
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Fig6: Double-labeled neurons expressing NeuN and OPN. See staining paradigm as given in figure legend 1. a case 16, normal; b case 25, ALS; c case 18, MND; d case 20, ANI; e case 21, MND/HAD; f case 13, HAD

Mentions: In HIV+ and ALS samples, NeuN reactivity was localized in the nucleus as well as in the cytoplasm (Lucas et al. 2014), while OPN staining was restricted to the cytoplasm of neuronal cell bodies (Fig. 5). Unexpectedly, abundant OPN reactive NeuN+ neurons were readily detectable in many of the normal uninfected controls (Fig. 6a). OPN levels were highest in the HIV+ ANI cases (1.706 ± 1.045, n = 6) compared to all other groups (normal, 1.394 ± 0.748, p = 0.005, n = 10; HIV+ MND/HAD, 1.428 ± 0.589, p = 0.023, n = 8; ALS, 1.226 ± 0.862, p < 0.0001, n = 5) (Fig. 7). Based on the NeuN/OPN ratio, the ALS group (1.134 ± 0.632) had significantly more NeuN-reactive neurons compared to the normal (0.93 ± 0.59, p = 0.018), HIV+ ANI (0.844 ± 0.614, p = 0.001), and HIV+ MND/HAD groups (0.836 ± 0.438, p = 0.0002), which were similar to each other (Fig. 7b). These results suggest that neurons in cases from HIV+ ANI produce, on average, more OPN than all other groups.Fig. 5


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

Silva K, Hope-Lucas C, White T, Hairston TK, Rameau T, Brown A - J. Neurovirol. (2015)

Double-labeled neurons expressing NeuN and OPN. See staining paradigm as given in figure legend 1. a case 16, normal; b case 25, ALS; c case 18, MND; d case 20, ANI; e case 21, MND/HAD; f case 13, HAD
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Related In: Results  -  Collection

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Fig6: Double-labeled neurons expressing NeuN and OPN. See staining paradigm as given in figure legend 1. a case 16, normal; b case 25, ALS; c case 18, MND; d case 20, ANI; e case 21, MND/HAD; f case 13, HAD
Mentions: In HIV+ and ALS samples, NeuN reactivity was localized in the nucleus as well as in the cytoplasm (Lucas et al. 2014), while OPN staining was restricted to the cytoplasm of neuronal cell bodies (Fig. 5). Unexpectedly, abundant OPN reactive NeuN+ neurons were readily detectable in many of the normal uninfected controls (Fig. 6a). OPN levels were highest in the HIV+ ANI cases (1.706 ± 1.045, n = 6) compared to all other groups (normal, 1.394 ± 0.748, p = 0.005, n = 10; HIV+ MND/HAD, 1.428 ± 0.589, p = 0.023, n = 8; ALS, 1.226 ± 0.862, p < 0.0001, n = 5) (Fig. 7). Based on the NeuN/OPN ratio, the ALS group (1.134 ± 0.632) had significantly more NeuN-reactive neurons compared to the normal (0.93 ± 0.59, p = 0.018), HIV+ ANI (0.844 ± 0.614, p = 0.001), and HIV+ MND/HAD groups (0.836 ± 0.438, p = 0.0002), which were similar to each other (Fig. 7b). These results suggest that neurons in cases from HIV+ ANI produce, on average, more OPN than all other groups.Fig. 5

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street/Meyer 6-181, Baltimore, MD, 21287-7131, USA.

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 Ca(2+)-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.

Show MeSH
Related in: MedlinePlus