Cutting Edge: TNF-α Mediates Sensitization to ATP and Silica via the NLRP3 Inflammasome in the Absence of Microbial Stimulation

TLDR

The NLRP3 inflammasome activates caspase‑1 in response to danger signals and particulate matter, yet its role in sterile inflammation is uncertain because microbial pre‑stimulation is typically required. TNF‑α exposure enables ATP or silica to trigger caspase‑1 activation and IL‑1β secretion in macrophages and dendritic cells without microbial stimulation, a process dependent on TNF receptors, NLRP3, and ASC, and shows that TNF‑tolerized macrophages remain responsive to ATP, revealing a mechanism for sterile inflammation via the NLRP3 inflammasome.

Abstract

The Nlrp3 inflammasome is critical for the activation of caspase-1 in response to danger signals and particulate matter. However, its role in sterile inflammation remains unclear because prestimulation of phagocytic cells with microbial molecules is required for caspase-1 activation. We show here that exposure of macrophages and dendritic cells to TNF-alpha promotes ATP- or silica-mediated caspase-1 activation and IL-1beta secretion in the absence of microbial stimulation. The effect of TNF-alpha was abolished in macrophages deficient in TNF receptor I and II, Nlrp3, or ASC, whereas that induced by TLR ligands required MyD88/Trif. In addition to TNF-alpha, IL-1alpha and IL-1beta promoted caspase-1 activation via Nlrp3 in response to ATP. Remarkably, macrophages tolerized to TNF-alpha, but not to LPS, retained full sensitivity to ATP stimulation via Nlrp3. These results provide a mechanism by which danger signals and particulate matter mediate inflammation via the Nlrp3 inflammasome in the absence of microbial infection.