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

Abstract

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.

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

“…Our previous study showed activated autophagy and increased autophagosomes in AMs of silicosis patients and mouse model [13,15]. Studies reported that inhibition of autophagy in macrophages could relieve CS-induced pulmonary fibrosis [58,59]. However, Atg5 knockdown in mice showed that impairment of autophagy aggravated CS-induced pulmonary inflammation and fibrosis [14,15].…”

Autophagy and inflammation in chronic respiratory disease

“…108 Rapamycin treatment has demonstrated antifibrotic abilities in murine bleomycin-mediated mortality and fibrosis 95,102 . However, rapamycin appears to enhance the effects induced by silicon dioxide 109 and IPF patients taking the rapamycin analog everolimus have progression of disease. 110 Again, further studies are required to evaluate the benefits of targeting autophagy in IPF and whether or not these targeting strategies should be cell type-specific.…”

Diagnostic performance of distinct metabolic features in the plasma of patients with silicosis

“…Crystalline silica entering the airways is engulfed by macrophages, causing necrosis of the phagocytes, and then, the internalized silica is released again and engulfed by other macrophages. The repeated process of phagocytosis, necrosis and rephagocytosis of the cells induces in ammation and activation of the reactive oxygen species system, which is associated with pulmonary interstitial brosis [19,20]. Some metabolites in the pathogenesis of silicosis may play a predictive role in the diagnosis and severity of the disease.…”