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

Haijun Liu,Wei Zhang,Shencun Fang,Jian Yang,Zewei Zhou,Wei Wang,Honghong Yao,Yusi Cheng,Jie Chao,Hong Liao,Bing Han

doi:10.1038/cddis.2017.78

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 SiO2in 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.

Highlights

Following inhalation into the lungs, silica particles are engulfed by alveolar macrophages, which triggers endogenous or exogenous apoptosis signaling pathways
To evaluate whether SiO2 administration resulted in the activation and apoptosis of U937-derived macrophages (UDMs), western blot was performed to detect M1 and M2 marker proteins, including NOS2, ARG1 (Arginase 1), and SOCS3
A previous study reported that SiO2 induced alveolar macrophage apoptosis by extrinsic pathways in silicosis;[3] whether U937 cell-derived macrophages (UDMs) would undergo apoptosis after treatment with SiO2 remained unknown

Summary

Introduction

Following inhalation into the lungs, silica particles are engulfed by alveolar macrophages, which triggers endogenous or exogenous apoptosis signaling pathways. In the mouse model of silicosis, Bbc[3] 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. Macrophage activation may occur in response to of diverse external stimuli; activated macrophages differentiate into distinct subpopulations, including proinflammatory/cytotoxic M1 and anti-inflammatory/pro-fibrotic M2 macrophages.[8] These different phenotypes may play distinct roles in different types of immune responses both in vivo and in vitro.[9] It has been reported[10] that the transformation of alveolar macrophages into M1 and M2 phenotypes is associated with the development and progression of silicosis; the precise etiology of this mechanism remains to be explored

Methods

Results

Conclusion