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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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Osteopontin (OPN) expression in Iba1/AIF-1+ microglia. See staining paradigm as given in figure legend 1. a case 16, normal; b case 4, normal; c case 29, ALS; d case 23, ANI; e case 12, MND; f case 13, HAD
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Fig3: Osteopontin (OPN) expression in Iba1/AIF-1+ microglia. See staining paradigm as given in figure legend 1. a case 16, normal; b case 4, normal; c case 29, ALS; d case 23, ANI; e case 12, MND; f case 13, HAD

Mentions: Microglia stained for Iba-1/AIF-1 displayed a variety of morphologies including ramified and ameboid shapes with varying degrees of processes (Fig. 3). Unexpectedly, abundant Iba-/AIF-1 staining was seen in several samples from the normal control group (Fig. 3a–b, cases 16 and 4). In addition, there was abundant Iba-1/AIF-1 reactivity in samples from the ALS group with distinctive labeling of microglia with extended ramified shapes (Fig. 3c, case 29). OPN levels in microglia were significantly elevated compared to normal controls (0.758 ± 0.376, n = 9) for ALS (1.356 ± 0.848, p < 0.0001, n = 5), HIV+ ANI (1.463 ± 0.934, p < 0.0001, n = 5), and HIV+ MND/HAD (1.467 ± 0.721, p < 0.0001, n = 5), but there were no differences between the disease groups (Fig. 4a). The level of Iba-I/AIF-1 normalized to OPN intensity was significantly lower in the disease groups (HIV+ ANI, 0.969 ± 0.570, p < 0.0001; HIV+ MND/HAD, 0.829 ± 0.358, p < 0.0001; ALS, 1.094 ± 0.782, p < 0.0001) compared to the normal controls (1.741 ± 1.21) (Fig. 4b). These results suggest that the amount of OPN expression per microglia was significantly elevated in the diseased groups compared to the normal controls.Fig. 3


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)

Osteopontin (OPN) expression in Iba1/AIF-1+ microglia. See staining paradigm as given in figure legend 1. a case 16, normal; b case 4, normal; c case 29, ALS; d case 23, ANI; e case 12, MND; f case 13, HAD
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: Osteopontin (OPN) expression in Iba1/AIF-1+ microglia. See staining paradigm as given in figure legend 1. a case 16, normal; b case 4, normal; c case 29, ALS; d case 23, ANI; e case 12, MND; f case 13, HAD
Mentions: Microglia stained for Iba-1/AIF-1 displayed a variety of morphologies including ramified and ameboid shapes with varying degrees of processes (Fig. 3). Unexpectedly, abundant Iba-/AIF-1 staining was seen in several samples from the normal control group (Fig. 3a–b, cases 16 and 4). In addition, there was abundant Iba-1/AIF-1 reactivity in samples from the ALS group with distinctive labeling of microglia with extended ramified shapes (Fig. 3c, case 29). OPN levels in microglia were significantly elevated compared to normal controls (0.758 ± 0.376, n = 9) for ALS (1.356 ± 0.848, p < 0.0001, n = 5), HIV+ ANI (1.463 ± 0.934, p < 0.0001, n = 5), and HIV+ MND/HAD (1.467 ± 0.721, p < 0.0001, n = 5), but there were no differences between the disease groups (Fig. 4a). The level of Iba-I/AIF-1 normalized to OPN intensity was significantly lower in the disease groups (HIV+ ANI, 0.969 ± 0.570, p < 0.0001; HIV+ MND/HAD, 0.829 ± 0.358, p < 0.0001; ALS, 1.094 ± 0.782, p < 0.0001) compared to the normal controls (1.741 ± 1.21) (Fig. 4b). These results suggest that the amount of OPN expression per microglia was significantly elevated in the diseased groups compared to the normal controls.Fig. 3

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