Exploring the role of macrophage polarization in the inflammatory response to inhaled particles: implications for mitochondrial and lysosomal function 4669

Abstract Description Macrophage polarization plays a key role in chronic lung inflammation caused by inhaled particles such as crystalline silica and engineered nanomaterials. Here, impact of macrophage polarization on mitochondrial and lysosomal function, particle uptake, and inflammatory signaling in a particle exposure was assessed to understand how macrophage polarization can drive inflammatory response in an inhaled particle exposure model. Murine ex vivo alveolar macrophages were polarized to M1 (IFNγ + LPS), M2a (IL4 + IL-13), and M2c (TGFβ + IL-10) macrophages. ROS production, lysosomal membrane permeabilization, and NLRP3 inflammasome activation, as indicated by IL-1β release, following particle exposure in each phenotype was evaluated. Lysosomal acid sphingomyelinase enzyme function and phagocytic uptake of particles was assessed in each polarization. Exposure to particles initiated ROS and lysosomal membrane permeabilization in all macrophage polarizations; however, M1 polarized macrophages demonstrated the lowest IL-1β release following exposure to crystalline silica or nickel oxide nanoparticles, which may be due to reduced particle uptake and decreased lysosomal membrane permeabilization when compared to M2a/M2c. These results demonstrate how macrophage polarization changes to mitochondrial and lysosomal function contribute to the inflammatory response to inhaled particles. Funding Sources Supported by NIH R25-ES002866 and NIH R01-ES033533. Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)