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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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CD68+ macrophages/microglia are readily detectable in normal control samples. ImageJ was used to quantify the area fraction of CD68 reactivity in three representative fields from each case. The mean and standard deviation and level of significance as determined by one-way ANOVA for normal controls and MND/HAD cases are shown. Category of clinical disorders (Table 2) at the time of death is indicated above the appropriate bars: GI gastrointestinal related, HCV hepatitis C virus
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Fig9: CD68+ macrophages/microglia are readily detectable in normal control samples. ImageJ was used to quantify the area fraction of CD68 reactivity in three representative fields from each case. The mean and standard deviation and level of significance as determined by one-way ANOVA for normal controls and MND/HAD cases are shown. Category of clinical disorders (Table 2) at the time of death is indicated above the appropriate bars: GI gastrointestinal related, HCV hepatitis C virus

Mentions: The high level of OPN, GFAP, and Iba-1/AIF-1 expression seen in the normal control group suggested the presence of injury and/or inflammation in the brain. To investigate this possibility, we stained sections with anti-CD68, which detects microglia, as well as perivascular, parenchymal, and resident macrophages (Esiri and McGee 1986), which typically have a finite lifespan in the brain and are not present in large numbers under normal homeostatic conditions (Esiri and O’D McGee 1986; Fischer-Smith et al. 2004). Strikingly, in 8 out of 10 normal cases, CD68+ macrophages/microglia were readily detectable throughout the cortical layers (Fig. 8). The level of CD68 reactivity was similar to or significantly exceeded that of HIV+ MND/HAD samples (case 1 vs. case 21, p = 0.0026; case 1 vs. case 22, p = 0.0101; case 14 vs. case 21, p = 0.0287; Fig. 9). Table 2 lists the cause of death for samples in the normal control group. In several cases, severe injury to the gastrointestinal tract (Fig. 9, cases 1, 4, and 24) and disorders of the lungs (Fig. 9, cases 2, 5, and 14) displayed the highest levels of CD68 staining, although there were no statistically significant differences between the normal samples with the exception of case 17 vs. case 1 (p = 0.0368). These results suggest that the majority of normal controls used in this study, although not infected with HIV, displayed evidence of exposure to an event(s) that promoted a sustained increase of CD68+ macrophages in the brain.Fig. 8


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)

CD68+ macrophages/microglia are readily detectable in normal control samples. ImageJ was used to quantify the area fraction of CD68 reactivity in three representative fields from each case. The mean and standard deviation and level of significance as determined by one-way ANOVA for normal controls and MND/HAD cases are shown. Category of clinical disorders (Table 2) at the time of death is indicated above the appropriate bars: GI gastrointestinal related, HCV hepatitis C virus
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4372685&req=5

Fig9: CD68+ macrophages/microglia are readily detectable in normal control samples. ImageJ was used to quantify the area fraction of CD68 reactivity in three representative fields from each case. The mean and standard deviation and level of significance as determined by one-way ANOVA for normal controls and MND/HAD cases are shown. Category of clinical disorders (Table 2) at the time of death is indicated above the appropriate bars: GI gastrointestinal related, HCV hepatitis C virus
Mentions: The high level of OPN, GFAP, and Iba-1/AIF-1 expression seen in the normal control group suggested the presence of injury and/or inflammation in the brain. To investigate this possibility, we stained sections with anti-CD68, which detects microglia, as well as perivascular, parenchymal, and resident macrophages (Esiri and McGee 1986), which typically have a finite lifespan in the brain and are not present in large numbers under normal homeostatic conditions (Esiri and O’D McGee 1986; Fischer-Smith et al. 2004). Strikingly, in 8 out of 10 normal cases, CD68+ macrophages/microglia were readily detectable throughout the cortical layers (Fig. 8). The level of CD68 reactivity was similar to or significantly exceeded that of HIV+ MND/HAD samples (case 1 vs. case 21, p = 0.0026; case 1 vs. case 22, p = 0.0101; case 14 vs. case 21, p = 0.0287; Fig. 9). Table 2 lists the cause of death for samples in the normal control group. In several cases, severe injury to the gastrointestinal tract (Fig. 9, cases 1, 4, and 24) and disorders of the lungs (Fig. 9, cases 2, 5, and 14) displayed the highest levels of CD68 staining, although there were no statistically significant differences between the normal samples with the exception of case 17 vs. case 1 (p = 0.0368). These results suggest that the majority of normal controls used in this study, although not infected with HIV, displayed evidence of exposure to an event(s) that promoted a sustained increase of CD68+ macrophages in the brain.Fig. 8

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