Inflammasome activation in nanoparticle-induced lung inflammation.
Holian-A; Hamilton-RF; Wu-N; Porter-DW; Tsuruoka-S; Mitra-S; Girtsman-TA
Toxicologist 2014 Mar; 138(1):386
The precise mechanisms responsible for engineered nanomaterial (ENM)-induced activity remain to be elucidated. Increasing evidence supports the notion that alveolar macrophages (AM) contribute to ENM-induced lung inflammation and pathology through the NLRP3 Inflammasome in a similar manner as has been implicated for a number of "danger" crystals in a process sometimes referred to as sterile inflammation. In order to characterize mechanisms involved in ENM inflammation studies have been conducted in vitro using THP-1 and NLRP3 KO cells and primary AM from mice and humans as well as in vivo studies using murine models. Two key steps regulate this process: 1) ENM-induced phagolysosomal membrane permeability (LMP) leading to the release of cathepsin B into the cytoplasm, which has been linked to NLRP3 Inflammasome assembly and Caspase-1 activation necessary for IL-1beta to be cleaved from its pro-form, and 2) elimination of the NLRP3 Inflammasome complex by autophagy. The precise steps leading to LMP have not been defined, although generation of reactive oxygen species and/or some other property of ENM have been implicated. Acidification of lysosomes is necessary for LMP since imipramine and chloroquine can block NLRP3 Inflammasome activation and downstream inflammation. ENM length and surface characteristics of ENM are important factors in LMP. Increasing the aspect ratio and/or rigidity of ENM increases bioactivity, while carboxylation of ENM surfaces decreases bioactivity. Furthermore, while ENM induce autophagy, increasing autophagic flux can block IL-1beta release from macrophages. Finally, comparing the outcomes from in vitro and in vivo studies suggest that IL-1beta production from THP-1 cells can be used to predict in vivo outcomes and serve to prioritize in vivo studies.
Toxicology; Air-quality; Exposure-levels; Workers; Work-environment; Environmental-exposure; Nanotechnology; Lung; Lung-disorders; Lung-function; Respiration; Respiratory-system-disorders; Respiratory-irritants; Pulmonary-system; Pulmonary-system-disorders; Pulmonary-function; Pathology; In-vitro-studies
The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona