Lipopolysaccharide sensitizes microglia toward Ca2+‐induced cell death: Mode of cell death shifts from apoptosis to necrosis

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Abstract
Little is known about the effect of microglial activation on cell death. This study examines the effects of lipopolysaccharide (LPS) and interferon‐γ (IFN‐γ), triggers of microglial activation, on cell death induced by several agents in cultured rat microglia. For comparison, the effect of LPS on cell death is also examined in cultured astrocytes. LPS or IFN‐γ enhanced cell death induced by thapsigargin or ionomycin, an agent that increases intracellular Ca2+ concentration, although LPS or IFN‐γ alone did not affect cell viability. Thapsigargin or ionomycin induced apoptosis in LPS‐untreated microglia, while they induced necrosis in LPS‐treated microglia, which were partially reversed by O,O′‐bis(2‐aminophenyl)ethyleneglycol‐N,N,N′,N′‐tetraacetic acid tetraacetoxymethyl ester (BAPTA‐AM, an intracellular Ca2+ chelator). In contrast, LPS treatment did not affect tunicamycin‐ or staurosporine‐induced apoptosis, while it inhibited S‐nitroso‐N‐acetylpenicillamine‐induced apoptosis. The effect of LPS on thapsigargin or ionomycin‐induced apoptosis was not observed in astrocytes. These results indicate that microglial activation sensitizes the cells toward cell death induced by the change in intracellular Ca2+ concentration and shifts the mode of cell death from apoptosis to necrosis.