NLRP3 inflammasome activation in murine alveolar macrophages and related lung pathology is associated with MWCNT nickel contamination

Abstract

Multi-walled carbon nanotubes (MWCNT) have been reported to cause lung pathologies in multiple studies. However, the mechanism responsible for the bioactivity has not been determined. This study used nine different well-characterized MWCNT and examined the outcomes in vitro and in vivo. MWCNT, from a variety of sources that differed primarily in overall purity and metal contaminants, were examined for their effects in vitro (toxicity and NLRP3 inflammasome activation using primary alveolar macrophages isolated from C57Bl/6 mice). In addition, in vivo exposures were conducted to determine the inflammatory and pathogenic potency. The particles produced a differential magnitude of responses, both in vivo and in vitro, that was associated most strongly with nickel contamination on the particle. Furthermore, the mechanism of action for the Ni-contaminated particles was in their ability to disrupt macrophage phagolysosomes, which resulted in NLRP3 activation and subsequent cytokine release associated with prolonged inflammation and lung pathology.

Keywords::

• Inflammasome
• multi-walled carbon nanotubes
• nickel
• macrophage
• NLRP3

Acknowledgments

We would like to thank Dr Jim Driver at the University of Montana Electron Microscopy Facility (Division of Biological Sciences), for the EM images of the AM cells and Mr Erik Hill for providing technical assistance. Mr Kevin Trout produced the artwork in Figure 10. The authors are indebted to Dr Nigel Walker and the National Toxicology Program of NIEHS for providing the MWCNT. Furthermore, the authors are indebted to the Research Triangle Institute for the characterization of the MWCNT.

Declaration of interest

This work was supported by the National Institutes of Health [R01 ES015497 andRC2 ES018742] and COBRE [P20 RR017670]. The authors report no declaration of interest.