Different shapes of Al2O3 particles induce differential cytotoxicity via a mechanism involving lysosomal destabilization and reactive oxygen species generation

Abstract

The biological effects of nano- and micro-sized Al2O3 particles are hypothesized to differ according to the shapes as well as the sizes of the particles. Thus, the mechanisms of interleukin (IL)-1β production and the association between the shape of the Al2O3 particle and its cytotoxicity in macrophage-like THP-1 cells were investigated using particles with three different shapes [N-Al2O3 (<30 nm), S-Al2O3 (2-4 nm × 100-800 nm), L-Al2O3 (2-4 nm × 2800 nm)]. Levels of IL-1β production and cytotoxicity were concentration-dependent and were in the following order: S-Al2O3 > N-Al2O3 > L-Al2O3. Stimulus of THP-1 cells by Al2O3 particles led to lysosomal destabilization, generation of intracellular reactive oxygen species (ROS), and subsequent release of cathepsin B. The magnitude of the stimulus was dependent on the shapes and aspect ratios of the particles. Additional results suggested that caspase-1 (NALP3 inflammasome) activation and IL-1β production followed cathepsin B release. In addition, the cell death induced by Al2O3 particles was closely related with cathepsin B leakage. The mode of cell death was necrotic as much as apoptotic. We conclude that Al2O3 particles induce different levels of IL-1β production and cytotoxicity depending on their particle shapes or aspect ratios. The current finding may support the development of safe forms of Al2O3 particles.