The role of NLRP3 inflammasome activation in proinflammatory and cytotoxic effects of metal nanoparticles

Feb 17, 2025Archives of toxicology

How activation of the NLRP3 inflammasome links metal nanoparticles to inflammation and cell damage

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Abstract

NLRP3 inflammasome activation is associated with inflammatory responses induced by metal nanoparticles.

Various metal nanoparticles, including titanium, zinc, and silver, can activate the NLRP3 inflammasome across multiple cell types.
In vivo studies indicate that NLRP3 pathway activation is involved in inflammation-related conditions such as colitis and neuroinflammation caused by metal nanoparticles.
The activation process involves particle endocytosis, lysosomal damage, reactive oxygen species (ROS) formation, and increased intracellular calcium levels.
Caspase-1 activation leads to the maturation of proinflammatory cytokines IL-1β and IL-18, while gasdermin D cleavage contributes to cell death.
Smaller and rod-shaped metal nanoparticles may have a stronger impact on NLRP3 inflammasome activation, although some contradictory findings exist.

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Exposure to metal nanoparticles (NPs) is known to induce inflammatory responses in various tissues, thus limiting their therapeutic potential. NOD-like receptor protein 3 (NLRP3) inflammasome activation is an essential component of innate immunity playing a significant role in inflammation and development of inflammatory diseases. Therefore, the objective of the present review was to summarize data on the role of NLRP3 inflammasome in proinflammatory effects induced by metal NPs, and to discuss the underlying molecular mechanisms, including its dependence on the physical and chemical properties of metal NPs. Titanium, zinc, silver, aluminum, iron, cobalt, nickel, vanadium, and tungsten nanoparticles, as well as metal-based quantum dots have all been shown to induce NLRP3 inflammasome activation in vitro in macrophages and monocytes, dendritic cells, keratinocytes, hepatocytes, enterocytes, microglia, astrocytes, lung epithelial cells, endotheliocytes, as well as certain types of cancer cells. In vivo studies confirmed the role of NLRP3 pathway activation in development of colitis, pulmonary inflammation, liver damage, osteolysis, and neuroinflammation induced by various metal nanoparticles. Briefly, particle endocytosis with subsequent lysosomal damage, induction of ROS formation, Kefflux, increased intracellular Calevels, and NF-κB pathway activation results in NLRP3 inflammasome complex assembly, caspase-1 activation, and cleavage of pro-IL-1β and pro-IL-18 to mature proinflammatory cytokines, while gasdermin D cleavage induces pyroptotic cell death. Moreover, small-sized and rod-shaped metal NPs exert a more profound stimulatory effect on NLRP3 inflammasome activation, but contrary findings have also been reported. Taken together, it is concluded that NLRP3 inflammasome may mediate both adverse proinflammatory effects of metal nanoparticles, as well as their beneficial effect when used as antitumor agents. + 2+

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