Extracellular cardiolipin modulates microglial phagocytosis and cytokine secretion in a toll-like receptor (TLR) 4-dependent manner.

Microglia-driven neuroinflammation contributes to neurodegenerative diseases. Mitochondrial phospholipid cardiolipin acts as a signaling molecule when released from damaged cells. We demonstrate that extracellular cardiolipin induces the secretion of monocyte chemoattractant protein-1 and interferon gamma-induced protein 10 by resting microglia while inhibiting secretion of cytokines by microglia stimulated with lipopolysaccharide, amyloid Aβ42 peptides, or α-synuclein. Extracellular cardiolipin also induces nitric oxide secretion by microglia-like cells and upregulates microglial phagocytosis. By using blocking antibodies, we determine that toll-like receptor 4 mediates the latter effect. Under physiological and pathological conditions characterized by cell death, extracellularly released cardiolipin may regulate immune responses of microglia.