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.