Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: Mechanism for removal of apoptotic cells in the inflamed nervous system

Apoptosis of autoaggressive T cells in the central nervous system (CNS) is an effective, nonphlogistic mechanism for the termination of autoimmune inf lammation in experimental autoimmune encephalomyelitis (EAE). The clearance of apoptotic leukocytes by tissue-specific phagocytes is a critical event in the resolution of the inflammatory attack. To investigate the role of mi croglia in the removal of apoptotic cells and potential regulatory mechanis ms of microglial phagocytosis, an in vitro phagocytosis assay was establish ed, using Lewis rat microglia. Microglia exhibited a high capacity for the uptake of apoptotic autologous thymocytes, as well as apoptotic encephalito genic myelin basic protein (MBP)-specific T cells, in contrast to nonapopto tic target cells. Pretreatment of microglia with interferon-gamma (IFN-gamm a) raised the proportion of microglia capable of phagocytosing apoptotic ce lls to 75% above the untreated controls. The increased phagocytic activity was selective for apoptotic target cells and was not dependent on phosphati dylserine-mediated recognition mechanisms. In contrast, preincubation of mi croglia with interleukin-4 (IL-4) inhibited the uptake of apoptotic cells, whereas tumor-necrosis factor-alpha (TNF-alpha) and transforming growth fac tor-beta (TGF-beta) did not alter phagocytosis. Phagocytic clearance of apo ptotic inflammatory cells by microglia may be an important mechanism for th e termination of autoimmune inflammation in the CNS. Augmentation of microg lial phagocytosis by the Th-1-type cytokine IFN-gamma suggests a feedback m echanism for the accelerated clearance of the inflammatory infiltrate in th e CNS. GLIA 33:87-95, 2001. (C) 2001 Wiley-Liss, Inc.