BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis

Following inhalation into the lungs, silica particles are engulfed by alveolar macrophages, which triggers endogenous or exogenous apoptosis signaling pathways. As an inducer of apoptosis, the role of BBC3/PUMA (BCL2-binding component 3) in macrophages during silicosis remains unknown. Here, we exposed U937 cell-derived macrophages (UDMs) to SiO2 in vitro to explore the function of BBC3 in SiO2-induced disease. We found that SiO2 induced increased BBC3 expression, as well as macrophage activation and apoptosis. Knockdown of Bbc3 with specific siRNA significantly mitigated the SiO2-induced effects. In addition, our results clearly showed increased levels of autophagy in macrophages exposed to SiO2. However, inhibition of BBC3 decreased the occurrence of autophagy. Furthermore, we observed that the blockade of autophagy with 3-MA, an autophagy inhibitor, inhibited SiO2-induced macrophage activation and apoptosis. In contrast, rapamycin, an autophagy inducer, further enhanced the effects induced by SiO2. The conditioned medium from macrophages exposed to SiO2 promoted the proliferation and migration of fibroblasts, and the inhibition of BBC3/autophagy reduced the effects of the conditioned medium on fibroblasts. In the mouse model of silicosis, Bbc3 knockout mice clearly exhibited decreased levels of autophagy and fibrosis progression. These results suggest that downregulation of BBC3 expression may become a novel therapeutic strategy for the treatment of silicosis.