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Understanding the MIND phenotype: macrophage/microglia inflammation in neurocognitive disorders related to human immunodeficiency virus infection.

Brown A - Clin Transl Med (2015)

Bottom Line: Inflammatory signaling is required for regenerative repair, healing, and pathogen clearance functions.In this regard, non-human primate models for human immunodeficiency virus have been extremely useful for understanding the contribution of bone marrow-derived monocytes in neurological disease and their interaction and impact on the activation state of resident microglia in the brain.Recent insights on macrophage phenotype and persistent inflammation in the brain in HIV-associated neurocognitive disorder from immunohistochemical studies on human autopsy tissue will be examined.

View Article: PubMed Central - PubMed

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

ABSTRACT
Tissue macrophages play important roles in maintaining homeostasis in most organs of the body including the brain where microglia represent the resident phagocytic cells of this compartment. The possibility of one day harnessing macrophage plasticity to treat or ameliorate disorders including obesity, cancer, organ damage, intestinal disorders, neurodegeneration, and cardiovascular disease in which these cells play a role, is a very exciting prospect. Inflammatory signaling is required for regenerative repair, healing, and pathogen clearance functions. However, when the inflammatory response persists in a chronic fashion over an extended period of time, damage to neurons is followed by neuronal injury and dysfunction. Macrophages in the brain are heterogeneous arising from tissues during embryogenesis, and in the adult, from bone marrow derived monocytes that enter through the blood-brain-barrier. While much of our insight regarding macrophage functional subtypes has been garnered through elegant studies in mice, which are amenable to genetic manipulation, far less is known about such cells in human tissues, and particularly in the brain under normal, disease, or injurious conditions. In this regard, non-human primate models for human immunodeficiency virus have been extremely useful for understanding the contribution of bone marrow-derived monocytes in neurological disease and their interaction and impact on the activation state of resident microglia in the brain. This review will focus on what has been learned from the rhesus macaque models about the types of macrophages present in the brains of animals with encephalitis. In vitro studies, which have used human blood monocytes differentiated into macrophages to address the question of macrophage subsets in HIV infection will be highlighted. Recent insights on macrophage phenotype and persistent inflammation in the brain in HIV-associated neurocognitive disorder from immunohistochemical studies on human autopsy tissue will be examined.

No MeSH data available.


Related in: MedlinePlus

Abundant Iba1/AIF-1 positive parenchymal and perivascular macrophage/microglia (red color) costain for osteopontin (OPN) (brown color) expression in tissue from the occipital lobe of an HIV-infected individual with asymptomatic neurocognitive impairment (ANI). Paraffinembedded human autopsy tissue from the occipital lobe (National NeuroAIDS Tissue Consortium). Antigen retrieval was performed in citric acid buffer pH 6.0 and slides were stained sequentially with rabbit polyclonal antisera against Iba1/AIF-1 (SIGMA) overnight at 4°C followed by incubation with goat-anti-rabbitalkaline phosphatase (AP) secondary for 1 hr at room temperature and developed with permanent FastRed Quanto (ThermoFisher) (red color). Slides were then incubated with mouse monoclonal antibody to OPN (MAB194, Maine Biotechnology) at room temperature for 2 hrs followed by goat anti-mouse-horse radish peroxidase for 1 hr and developed with 3,3’-diaminobenzidine (brown color). Images were taken on an Axio Observer A1 inverted microscope (Zeiss) at 20x magnification. Adjustment of the image brightness, contrast and sharpness was performed with Adobe Photoshop 5.5 using the same settings for each image.
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Fig1: Abundant Iba1/AIF-1 positive parenchymal and perivascular macrophage/microglia (red color) costain for osteopontin (OPN) (brown color) expression in tissue from the occipital lobe of an HIV-infected individual with asymptomatic neurocognitive impairment (ANI). Paraffinembedded human autopsy tissue from the occipital lobe (National NeuroAIDS Tissue Consortium). Antigen retrieval was performed in citric acid buffer pH 6.0 and slides were stained sequentially with rabbit polyclonal antisera against Iba1/AIF-1 (SIGMA) overnight at 4°C followed by incubation with goat-anti-rabbitalkaline phosphatase (AP) secondary for 1 hr at room temperature and developed with permanent FastRed Quanto (ThermoFisher) (red color). Slides were then incubated with mouse monoclonal antibody to OPN (MAB194, Maine Biotechnology) at room temperature for 2 hrs followed by goat anti-mouse-horse radish peroxidase for 1 hr and developed with 3,3’-diaminobenzidine (brown color). Images were taken on an Axio Observer A1 inverted microscope (Zeiss) at 20x magnification. Adjustment of the image brightness, contrast and sharpness was performed with Adobe Photoshop 5.5 using the same settings for each image.

Mentions: HIV-associated neurocognitive disorders (HAND) is an umbrella term to describe three levels of neurocognitive dysfunction: asymptomatic neurocognitive impairment (ANI) in which individuals show deficits (greater than one standard deviation) in two or more cognitive domains, but no impairment of activities of daily living (ADL); minor neurocognitive disorder has the same level of impairment as ANI, but ADLs are mildly affected and HIV-associated dementia (HAD) represents the most severe form of impairment in which deficits in two or more cognitive domains is greater than two standard deviations and there are a severe impact on ADLs [75,76]. In tissue from an HIV-infected individual with ANI, with very low viral load in the CSF (19 RNA copies/ml) or plasma (249 RNA copies/ml) who had been on antiretrovirals, an abundance of double-stained Iba-1/OPN perivascular macrophages and microglia and parenchymal microglia were detected (Figure 1). In a case with MND, the microglia appear to be predominantly of the ameboid type with few ramified processes (Figure 2). This patient at death despite being on therapy had a plasma viral load of >48,000 copies/ml, a CSF load of 148 copies/ml and was severely immunosuppressed with a CD4 T-cell count of 10. A case with HAD displayed microgliosis with abundant ameboid and ramified microglia in the parenchyma, and a high level of OPN expression (Figure 3). This individual at death had a high plasma viral load of ~40,000 copies/ml, a CSF load of 2747 copies/ml but a CD4 T-cell level of 299, not indicative of immunosuppression. Another study also found, as detected by the markers CD16, CD163, HLA-DR, and GFAP, that for macrophages/microglia and astrocytes, elevated levels of inflammation in the brain remained a common feature in HIV-infected individuals without evidence of encephalitis or productive viral replication in the brain [77]. Together these results highlight the variation in microglia activation that persists in the brain at the individual level and the need for reliable plasma and/or CSF markers that would allow clinicians to track smoldering CNS inflammation.Figure 1


Understanding the MIND phenotype: macrophage/microglia inflammation in neurocognitive disorders related to human immunodeficiency virus infection.

Brown A - Clin Transl Med (2015)

Abundant Iba1/AIF-1 positive parenchymal and perivascular macrophage/microglia (red color) costain for osteopontin (OPN) (brown color) expression in tissue from the occipital lobe of an HIV-infected individual with asymptomatic neurocognitive impairment (ANI). Paraffinembedded human autopsy tissue from the occipital lobe (National NeuroAIDS Tissue Consortium). Antigen retrieval was performed in citric acid buffer pH 6.0 and slides were stained sequentially with rabbit polyclonal antisera against Iba1/AIF-1 (SIGMA) overnight at 4°C followed by incubation with goat-anti-rabbitalkaline phosphatase (AP) secondary for 1 hr at room temperature and developed with permanent FastRed Quanto (ThermoFisher) (red color). Slides were then incubated with mouse monoclonal antibody to OPN (MAB194, Maine Biotechnology) at room temperature for 2 hrs followed by goat anti-mouse-horse radish peroxidase for 1 hr and developed with 3,3’-diaminobenzidine (brown color). Images were taken on an Axio Observer A1 inverted microscope (Zeiss) at 20x magnification. Adjustment of the image brightness, contrast and sharpness was performed with Adobe Photoshop 5.5 using the same settings for each image.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4385031&req=5

Fig1: Abundant Iba1/AIF-1 positive parenchymal and perivascular macrophage/microglia (red color) costain for osteopontin (OPN) (brown color) expression in tissue from the occipital lobe of an HIV-infected individual with asymptomatic neurocognitive impairment (ANI). Paraffinembedded human autopsy tissue from the occipital lobe (National NeuroAIDS Tissue Consortium). Antigen retrieval was performed in citric acid buffer pH 6.0 and slides were stained sequentially with rabbit polyclonal antisera against Iba1/AIF-1 (SIGMA) overnight at 4°C followed by incubation with goat-anti-rabbitalkaline phosphatase (AP) secondary for 1 hr at room temperature and developed with permanent FastRed Quanto (ThermoFisher) (red color). Slides were then incubated with mouse monoclonal antibody to OPN (MAB194, Maine Biotechnology) at room temperature for 2 hrs followed by goat anti-mouse-horse radish peroxidase for 1 hr and developed with 3,3’-diaminobenzidine (brown color). Images were taken on an Axio Observer A1 inverted microscope (Zeiss) at 20x magnification. Adjustment of the image brightness, contrast and sharpness was performed with Adobe Photoshop 5.5 using the same settings for each image.
Mentions: HIV-associated neurocognitive disorders (HAND) is an umbrella term to describe three levels of neurocognitive dysfunction: asymptomatic neurocognitive impairment (ANI) in which individuals show deficits (greater than one standard deviation) in two or more cognitive domains, but no impairment of activities of daily living (ADL); minor neurocognitive disorder has the same level of impairment as ANI, but ADLs are mildly affected and HIV-associated dementia (HAD) represents the most severe form of impairment in which deficits in two or more cognitive domains is greater than two standard deviations and there are a severe impact on ADLs [75,76]. In tissue from an HIV-infected individual with ANI, with very low viral load in the CSF (19 RNA copies/ml) or plasma (249 RNA copies/ml) who had been on antiretrovirals, an abundance of double-stained Iba-1/OPN perivascular macrophages and microglia and parenchymal microglia were detected (Figure 1). In a case with MND, the microglia appear to be predominantly of the ameboid type with few ramified processes (Figure 2). This patient at death despite being on therapy had a plasma viral load of >48,000 copies/ml, a CSF load of 148 copies/ml and was severely immunosuppressed with a CD4 T-cell count of 10. A case with HAD displayed microgliosis with abundant ameboid and ramified microglia in the parenchyma, and a high level of OPN expression (Figure 3). This individual at death had a high plasma viral load of ~40,000 copies/ml, a CSF load of 2747 copies/ml but a CD4 T-cell level of 299, not indicative of immunosuppression. Another study also found, as detected by the markers CD16, CD163, HLA-DR, and GFAP, that for macrophages/microglia and astrocytes, elevated levels of inflammation in the brain remained a common feature in HIV-infected individuals without evidence of encephalitis or productive viral replication in the brain [77]. Together these results highlight the variation in microglia activation that persists in the brain at the individual level and the need for reliable plasma and/or CSF markers that would allow clinicians to track smoldering CNS inflammation.Figure 1

Bottom Line: Inflammatory signaling is required for regenerative repair, healing, and pathogen clearance functions.In this regard, non-human primate models for human immunodeficiency virus have been extremely useful for understanding the contribution of bone marrow-derived monocytes in neurological disease and their interaction and impact on the activation state of resident microglia in the brain.Recent insights on macrophage phenotype and persistent inflammation in the brain in HIV-associated neurocognitive disorder from immunohistochemical studies on human autopsy tissue will be examined.

View Article: PubMed Central - PubMed

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

ABSTRACT
Tissue macrophages play important roles in maintaining homeostasis in most organs of the body including the brain where microglia represent the resident phagocytic cells of this compartment. The possibility of one day harnessing macrophage plasticity to treat or ameliorate disorders including obesity, cancer, organ damage, intestinal disorders, neurodegeneration, and cardiovascular disease in which these cells play a role, is a very exciting prospect. Inflammatory signaling is required for regenerative repair, healing, and pathogen clearance functions. However, when the inflammatory response persists in a chronic fashion over an extended period of time, damage to neurons is followed by neuronal injury and dysfunction. Macrophages in the brain are heterogeneous arising from tissues during embryogenesis, and in the adult, from bone marrow derived monocytes that enter through the blood-brain-barrier. While much of our insight regarding macrophage functional subtypes has been garnered through elegant studies in mice, which are amenable to genetic manipulation, far less is known about such cells in human tissues, and particularly in the brain under normal, disease, or injurious conditions. In this regard, non-human primate models for human immunodeficiency virus have been extremely useful for understanding the contribution of bone marrow-derived monocytes in neurological disease and their interaction and impact on the activation state of resident microglia in the brain. This review will focus on what has been learned from the rhesus macaque models about the types of macrophages present in the brains of animals with encephalitis. In vitro studies, which have used human blood monocytes differentiated into macrophages to address the question of macrophage subsets in HIV infection will be highlighted. Recent insights on macrophage phenotype and persistent inflammation in the brain in HIV-associated neurocognitive disorder from immunohistochemical studies on human autopsy tissue will be examined.

No MeSH data available.


Related in: MedlinePlus