BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis
Haijun Liu1,2, Yusi Cheng2, Jian Yang2
1Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, China.
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.
Insights
Silica exposure activates macrophages, inducing apoptosis and autophagy via BBC3 (BCL2-binding component 3). Inhibiting BBC3 or autophagy reduces silicosis progression and lung fibrosis.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Toxicology
Background:
- Silicosis is a lung disease caused by silica particle inhalation.
- Macrophage apoptosis and autophagy are implicated in silicosis pathogenesis.
- The role of BBC3/PUMA in silica-induced macrophage responses is unclear.
Purpose of the Study:
- To investigate the function of BBC3 in silica-induced macrophage activation, apoptosis, and autophagy.
- To explore the therapeutic potential of targeting BBC3 in silicosis.
Main Methods:
- In vitro studies using U937 cell-derived macrophages exposed to SiO2.
- siRNA-mediated knockdown of Bbc3.
- Pharmacological inhibition and induction of autophagy (3-MA, rapamycin).
- In vivo studies using a mouse model of silicosis and Bbc3 knockout mice.
Main Results:
- SiO2 exposure increased BBC3 expression, macrophage activation, apoptosis, and autophagy.
- Bbc3 knockdown mitigated SiO2-induced effects.
- Autophagy inhibition reduced SiO2-induced macrophage activation and apoptosis.
- BBC3 and autophagy influenced fibroblast proliferation and migration.
- Bbc3 knockout mice showed reduced autophagy and fibrosis progression.
Conclusions:
- BBC3 plays a critical role in silica-induced macrophage responses and silicosis progression.
- Targeting BBC3 and modulating autophagy may offer a novel therapeutic strategy for silicosis.
