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Regulation of the phagocytic activity of astrocytes by neuroimmune mediators endogenous to the central nervous system.

ABSTRACT: The phagocytic activity of glial cells is essential for maintaining normal brain activity, and its dysfunction may contribute to the central nervous system (CNS) pathologies, including neurodegenerative diseases. Phagocytic activity is one of the well-established neuroimmune functions of microglia. Although emerging evidence indicates that astrocytes can also function as CNS phagocytes in humans and rodents, limited information is available about the molecular mechanism regulating this function. To address this knowledge gap, we studied modulation of the phagocytic activity of human U118 MG astrocytic cells and murine primary astrocytes by four CNS inflammatory mediators and bacterial endotoxin lipopolysaccharide (LPS). LPS and cytochrome c (CytC) upregulated, while interferon (IFN)-γ downregulated, phagocytosis of latex beads by human astrocytic cells and phagocytosis of synaptosomes by murine primary astrocytes. Interleukin (IL)-1β and tumor necrosis factor (TNF)-α had no effect on the phagocytic activity of human astrocytic cells but upregulated this function in murine astrocytes. Varying effects of combinations of the above inflammatory mediators were observed in these two cell types. LPS- and CytC-induced phagocytic activity of human astrocytic cells was partially mediated by activation of toll-like receptor 4 (TLR4). By monitoring other functions of astrocytes, we concluded there were no correlations between the effects of the mediators studied on astrocyte phagocytic activity and their secretion of cytokines, cytotoxins, or glutamate. Our study identified four candidate CNS regulators of astrocyte phagocytic activity. Future investigation of molecular mechanisms behind this regulation could identify novel therapeutic targets allowing modulation of this astrocyte-mediated clearance mechanism in CNS pathologies.

SUBMITTER: Yang SS

PROVIDER: S-EPMC10374099 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Regulation of the phagocytic activity of astrocytes by neuroimmune mediators endogenous to the central nervous system.

Yang Sijie Shirley SS Simtchouk Svetlana S Gibon Julien J Klegeris Andis A

PloS one 20230727 7

The phagocytic activity of glial cells is essential for maintaining normal brain activity, and its dysfunction may contribute to the central nervous system (CNS) pathologies, including neurodegenerative diseases. Phagocytic activity is one of the well-established neuroimmune functions of microglia. Although emerging evidence indicates that astrocytes can also function as CNS phagocytes in humans and rodents, limited information is available about the molecular mechanism regulating this function. ...[more]

PMID: 37498903

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Project description:BackgroundTauopathy in the central nervous system (CNS) is a histopathological hallmark of frontotemporal dementia (FTD) and Alzheimer's disease (AD). Although AD is accompanied by various ocular changes, the effects of tauopathy on the integrity of the cornea, which is densely innervated by the peripheral nervous system and is populated by resident dendritic cells, is still unknown. The aim of this study was to investigate if neuroimmune interactions in the cornea are affected by CNS tauopathy.MethodsCorneas from wild type (WT) and transgenic rTg4510 mice that express the P301L tau mutation were examined at 2, 6, 8, and 11 months. Clinical assessment of the anterior segment of the eye was performed using spectral domain optical coherence tomography. The density of the corneal epithelial sensory nerves and the number and field area of resident epithelial dendritic cells were assessed using immunofluorescence. The immunological activation state of corneal and splenic dendritic cells was examined using flow cytometry and compared between the two genotypes at 9 months of age.ResultsCompared to age-matched WT mice, rTg4510 mice had a significantly lower density of corneal nerve axons at both 8 and 11 months of age. Corneal nerves in rTg4510 mice also displayed a higher percentage of beaded nerve axons and a lower density of epithelial dendritic cells compared to WT mice. From 6 months of age, the size of the corneal dendritic cells was significantly smaller in rTg4510 compared to WT mice. Phenotypic characterization by flow cytometry demonstrated an activated state of dendritic cells (CD86+ and CD45+ CD11b+CD11c+) in the corneas of rTg4510 compared to WT mice, with no distinct changes in the spleen monocytes/dendritic cells. At 2 months of age, there were no significant differences in the neural or immune structures between the two genotypes.ConclusionsCorneal sensory nerves and epithelial dendritic cells were altered in the rTg4510 mouse model of tauopathy, with temporal changes observed with aging. The activation of corneal dendritic cells prior to the gradual loss of neighboring sensory nerves suggests an early involvement of corneal immune cells in tau-associated pathology originating in the CNS.

Dataset Information

Regulation of the phagocytic activity of astrocytes by neuroimmune mediators endogenous to the central nervous system.

Publications

Regulation of the phagocytic activity of astrocytes by neuroimmune mediators endogenous to the central nervous system.

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