Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.

Activation of the NLRP3 inflammasome leads to the production of bioactive interleukin (IL)-1β fostering atherosclerosis. The current dogma is that NLRP3 must be first primed by microbial stimuli, known as pathogen-associated molecular patterns (PAMPs), and then activated by either microbial or host-derived inflammatory cues. The mechanism that controls NLRP3 functioning in the context of non-communicable diseases lacking overt microbial infections remains debated. Here, we show that chronic exposure to atherosclerosis-associated oxidized phospholipids (oxPLs) simultaneously primes and activates NLRP3 independently of microbial cues. Mechanistically, chronic exposure to host-derived oxPLs activate the transcription factor NRF2, which is necessary and sufficient to prime and activate NLRP3 in a PAMP-independent manner. NRF2 chronic activation drives oxidized mitochondrial DNA to activate NLRP3. Ex vivo analyses of atherosclerotic plaques in mice and humans identify a population of monocytes-derived macrophages which activates NRF2 and expresses IL-1β. Overall, our data point to oxPL-dependent NRF2 activation as an all-in-one signal necessary and sufficient to prime and activate NLRP3, sustaining atherogenesis.