Nanoparticles (NPs) elicit sterile inflammation, but
the underlying
signaling pathways are poorly understood. Here, we report that human
monocytes are particularly vulnerable to amorphous silica NPs, as
evidenced by single-cell-based analysis of peripheral blood mononuclear
cells using cytometry by time-of-flight (CyToF), while silane modification
of the NPs mitigated their toxicity. Using human THP-1 cells as a
model, we observed cellular internalization of silica NPs by nanoscale
secondary ion mass spectrometry (nanoSIMS) and this was confirmed
by transmission electron microscopy. Lipid droplet accumulation was
also noted in the exposed cells. Furthermore, time-of-flight secondary
ion mass spectrometry (ToF-SIMS) revealed specific changes in plasma
membrane lipids, including phosphatidylcholine (PC) in silica NP-exposed
cells, and subsequent studies suggested that lysophosphatidylcholine
(LPC) acts as a cell autonomous signal for inflammasome activation
in the absence of priming with a microbial ligand. Moreover, we found
that silica NPs elicited NLRP3 inflammasome activation in monocytes,
whereas cell death transpired through a non-apoptotic, lipid peroxidation-dependent
mechanism. Together, these data further our understanding of the mechanism
of sterile inflammation.