A tandem activation of NLRP3 inflammasome induced by copper oxide nanoparticles and dissolved copper ion in J774A.1 macrophage.

For the first time, we reported that CuONPs exposure induced interleukin (IL)-1β-mediated inflammation via NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome in J774A.1 macrophage. Mechanistically, CuONPs activated NLRP3 inflammasome is a two-fold process. Firstly, CuONPs challenge caused lysosomal damage, along with the release of cathepsin B, which directly mediated the activation of NLRP3 inflammasomes. Interestingly, after the deposition in lysosomes, CuONPs may release copper ion due to the acidic environment of lysosomes. Consequently, the released copper ions significantly induced cellular oxidative stress and further mediated the activation of NLRP3 inflammasomes. Moreover, CuONPs exposure could prime J774A.1 macrophage to express pro-IL-1β through myeloid differentiation factor 88 (MyD88)-dependent Toll-like receptor 4 (TLR4) signal pathway subsequently activating nuclear transcription factor kappa B (NF-κB).