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

Dufies, O.; Di Gioia, M.; Spreafico, R.; Tan, P. J.; Springstead, J. R.; Prell, S. A.; Case, J.; Gao, C.; Wei, K. S.; Wu, H.; Zanoni, I.

doi:10.1101/2025.10.29.685328

bioRxiv · 10.1101/2025.10.29.685328

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

Dufies, O.·Di Gioia, M.·Spreafico, R.·Tan, P. J.·Springstead, J. R.·Prell, S. A.·Case, J.·Gao, C.·Wei, K. S.·Wu, H.·Zanoni, I.

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Abstract

Activation of the NLRP3 inflammasome leads to the production of bioactive interleukin (IL)-1{beta} 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-1{beta}. 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.

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Dufies, O., Di Gioia, M., Spreafico, R., Tan, P. J., Springstead, J. R., Prell, S. A., Case, J., Gao, C., Wei, K. S., Wu, H., Zanoni, I.. 2025-10-30. Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.. https://doi.org/10.1101/2025.10.29.685328

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