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

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.

Keywords: HIV-associated neurocognitive disorder; Macrophage polarization; Microglial activation; Neurodegeneration; Neuroinflammation; Neuronal dysfunction; Osteopontin; Proinflammatory cytokine.

Figure 1

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.

Figure 2

Iba1/AIF-1 positive parenchymal macrophage/microglia (red color) costain for osteopontin (OPN) (brown color) expression in tissue from the occipital lobe of an HIV-infected individual with minor neurocognitive disorder (MND). Microglia with ameboid morphology are more abundant than cells with a ramified phenotype.

Figure 3

Abundant expression of osteopontin (brown color) in Iba1/AIF-1 positive parenchymal and perivascular macrophage/microglia (red color) in tissue from the occipital lobe of an HIV-infected individual with HIV-associated dementia (HAD). Osteopontin in HIV-infected HAD cases were significantly elevated compared to normal controls [74].