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

J Neuroimmunol. 2021 Apr 15:353:577496. doi: 10.1016/j.jneuroim.2021.577496. Epub 2021 Jan 24.

Abstract

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.

Keywords: Alzheimer's disease; DAMPs; Neurodegeneration; Neuroinflammation; Neuroprotection; Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiolipins / immunology
  • Cardiolipins / metabolism*
  • Cytokines / immunology
  • Cytokines / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microglia / immunology
  • Microglia / metabolism*
  • Phagocytosis / physiology*
  • THP-1 Cells
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Cardiolipins
  • Cytokines
  • Toll-Like Receptor 4