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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 is significantly elevated in GFAP-reactive astrocytes from HIV+ MND/HAD cases compared to amyotrophic lateral sclerosis (ALS) samples. Ten images were taken at ×20 magnification from all four quadrants of the slides for each case (an equal amount of area), and the intensity (area fraction) of the label for OPN and GFAP were quantified using ImageJ. The results are expressed as the ratio of a OPN to GFAP or b GFAP to OPN. One-way ANOVA, with Tukey’s correction for multiple comparisons and significance of *p < 0.05, was determined with GraphPad Prism 6. Normal, ALS, amyotrophic lateral sclerosis, HIV-infected cases asymptomatic neurocognitive disorder (HIV+ ANI), and HIV-infected cases with minor neurocognitive disorder/HIV-associated dementia (HIV+ MND/HAD)
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Fig2: Osteopontin is significantly elevated in GFAP-reactive astrocytes from HIV+ MND/HAD cases compared to amyotrophic lateral sclerosis (ALS) samples. Ten images were taken at ×20 magnification from all four quadrants of the slides for each case (an equal amount of area), and the intensity (area fraction) of the label for OPN and GFAP were quantified using ImageJ. The results are expressed as the ratio of a OPN to GFAP or b GFAP to OPN. One-way ANOVA, with Tukey’s correction for multiple comparisons and significance of *p < 0.05, was determined with GraphPad Prism 6. Normal, ALS, amyotrophic lateral sclerosis, HIV-infected cases asymptomatic neurocognitive disorder (HIV+ ANI), and HIV-infected cases with minor neurocognitive disorder/HIV-associated dementia (HIV+ MND/HAD)

Mentions: GFAP reactivity was highest in the upper cortical layers in most samples and in some cases, positively stained cells were visible throughout all cortical layers (Fig. 1). In the HIV+ MND/HAD group, astrocytic cell bodies devoid of processes often predominated (Fig. 1, cases 19 and 20). Compared to the normal control group (0.612 ± 0.255, n = 9), OPN levels did not differ significantly with the other groups (HIV + NC, 0.576 ± 0.212, n = 5; HIV+ impaired, 0.682 ± 0.254, n = 5; ALS, 0.524 ± 0.207, n = 5), although there was a trend of increased OPN in the HIV+ MND/HAD group (Fig. 2a). A significant increase in the level of OPN between the HIV+ MND/HAD and the ALS group was detected (p = 0.011, Fig. 2). Normalization of GFAP levels to OPN revealed no significant differences in the expression of GFAP among the different groups (Fig. 2b; normal, 2.02 ± 1.10; HIV + ANI, 2.027 ± 0.898; HIV+ MND/HAD 1.722 ± 0.792; ALS, 2.231 ± 0.948). These results suggest that GFAP-reactive astrocytes in HAND express OPN, and while levels between HIV+ NC and HIV+ MND/HAD did not differ, astrocytes in the latter case produce significantly higher levels of OPN than what was seen in samples from individuals with ALS.Fig. 1


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 is significantly elevated in GFAP-reactive astrocytes from HIV+ MND/HAD cases compared to amyotrophic lateral sclerosis (ALS) samples. Ten images were taken at ×20 magnification from all four quadrants of the slides for each case (an equal amount of area), and the intensity (area fraction) of the label for OPN and GFAP were quantified using ImageJ. The results are expressed as the ratio of a OPN to GFAP or b GFAP to OPN. One-way ANOVA, with Tukey’s correction for multiple comparisons and significance of *p < 0.05, was determined with GraphPad Prism 6. Normal, ALS, amyotrophic lateral sclerosis, HIV-infected cases asymptomatic neurocognitive disorder (HIV+ ANI), and HIV-infected cases with minor neurocognitive disorder/HIV-associated dementia (HIV+ MND/HAD)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4372685&req=5

Fig2: Osteopontin is significantly elevated in GFAP-reactive astrocytes from HIV+ MND/HAD cases compared to amyotrophic lateral sclerosis (ALS) samples. Ten images were taken at ×20 magnification from all four quadrants of the slides for each case (an equal amount of area), and the intensity (area fraction) of the label for OPN and GFAP were quantified using ImageJ. The results are expressed as the ratio of a OPN to GFAP or b GFAP to OPN. One-way ANOVA, with Tukey’s correction for multiple comparisons and significance of *p < 0.05, was determined with GraphPad Prism 6. Normal, ALS, amyotrophic lateral sclerosis, HIV-infected cases asymptomatic neurocognitive disorder (HIV+ ANI), and HIV-infected cases with minor neurocognitive disorder/HIV-associated dementia (HIV+ MND/HAD)
Mentions: GFAP reactivity was highest in the upper cortical layers in most samples and in some cases, positively stained cells were visible throughout all cortical layers (Fig. 1). In the HIV+ MND/HAD group, astrocytic cell bodies devoid of processes often predominated (Fig. 1, cases 19 and 20). Compared to the normal control group (0.612 ± 0.255, n = 9), OPN levels did not differ significantly with the other groups (HIV + NC, 0.576 ± 0.212, n = 5; HIV+ impaired, 0.682 ± 0.254, n = 5; ALS, 0.524 ± 0.207, n = 5), although there was a trend of increased OPN in the HIV+ MND/HAD group (Fig. 2a). A significant increase in the level of OPN between the HIV+ MND/HAD and the ALS group was detected (p = 0.011, Fig. 2). Normalization of GFAP levels to OPN revealed no significant differences in the expression of GFAP among the different groups (Fig. 2b; normal, 2.02 ± 1.10; HIV + ANI, 2.027 ± 0.898; HIV+ MND/HAD 1.722 ± 0.792; ALS, 2.231 ± 0.948). These results suggest that GFAP-reactive astrocytes in HAND express OPN, and while levels between HIV+ NC and HIV+ MND/HAD did not differ, astrocytes in the latter case produce significantly higher levels of OPN than what was seen in samples from individuals with ALS.Fig. 1

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