The inflammasome is implicated in many inflammatory diseases including neurological diseases but has been primarily studied in the macrophage-myeloid lineage. Here we demonstrate a physiologic role for nucleotide-binding domain, leucine-rich repeat, CARD domain containing proteins, NLRC4 and NLRP3, in brain astrocytes and microglia under the sterile neuroinflammation condition. In vitro, lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits an inflammasome activation dependent on both NLRC4 and NLRP3 in microglia and astrocytes, which are central players in neuroinflammation. Canonical inflammasome components ASC and caspase-1 but not non-canonical inflammasome component caspase-11 is required for LPC-activated inflammasome. Mechanistically, LPC-activated inflammasome also requires cathepsin B protease, calcium mobilization …