Regulation of neuroinflammation by astrocyte-derived cholesterol

Neurodegeneration and its concomitant loss of cognitive function is associated with inflammation and an accumulation of lipids, in particular cholesterol. In the brain, cholesterol is made in astrocytes and transported to surrounding cells by apolipoprotein E (apoE). Elevated cholesterol promotes inflammation in peripheral tissues, but whether astrocyte cholesterol can drive inflammation in the brain is unclear. Here we show that pro-inflammatory cytokines induce cholesterol synthesis in astrocytes. The astrocytes release the cholesterol and immune cells take it up, which causes clustering of proinflammatory receptors in lipid rafts, perpetuating the inflammatory signal. Knockout of cholesterol synthesis in astrocytes blocks the production of inflammatory cytokines in an AD mouse brain and reduces neuroinflammation induced by peripheral injection of lipopolysaccharide (LPS) into the mouse. We conclude that astrocyte cholesterol is a paracrine signal to microglia and tissue-resident macrophages, resulting in increased neuroinflammation.