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Macrophage-derived exosomes mediate silica-induced pulmonary fibrosis by activating fibroblast in an endoplasmic reticulum stress-dependent manner |
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| Authors: | Xiaofeng Qin Xiaofang Lin Lang Liu Ying Li Xiang Li Zhenghao Deng Huiping Chen Hui Chen Zhiyuan Niu Zisheng Li Yongbin Hu |
| Institution: | 1. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China;2. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China
Contribution: Investigation (equal), Methodology (equal);3. Department of Occupational Diseases, Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha, China Contribution: Investigation (equal);4. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China Department of Pathology, Xiangya Hospital, Central South University, Changsha, China Contribution: Investigation (equal);5. Department of Pathology, Xiangya Hospital, Central South University, Changsha, China Contribution: Investigation (equal);6. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China Contribution: Investigation (equal) |
| Abstract: | Macrophages play a key role in silicosis, and exosomes are potent mediators of intercellular communication. This suggests that macrophage-derived exosomes have a potential contribution to the pathogenesis of silicosis. To investigate whether macrophage-derived exosomes promote or inhibit lung fibrosis, in vitro, silica-exposed macrophage-derived exosomes (SiO2-Exos) were collected and cocultured with fibroblasts. The expression of collagen I and α-SMA was evaluated. Furthermore, the endoplasmic reticulum (ER) stress markers BIP, XBP1s and P-eIF2α were assessed after treatment with or without the ER stress inhibitor 4-PBA. In vivo, mice were pre-treated with the exosome secretion inhibitor GW4869 prior to silica exposure. After sacrifice, lung tissues were histologically examined, and the expression of proinflammatory cytokines (TNF-α, IL-1β and IL-6) in bronchoalveolar lavage fluid (BALF) was measured. The results showed that the expression of collagen I and α-SMA was up-regulated after treatment with SiO2-Exos, accompanied by increased expression of BIP, XBP1s and P-eIF2α. Pre-treatment with 4-PBA reversed this effect. More importantly, an in vivo study demonstrated that pre-treatment with GW4869 decreased lung fibrosis and the expression of TNF-α, IL-1β and IL-6 in BALF. These results suggested that SiO2-Exos are profibrogenic and that the facilitating effect is dependent on ER stress. |
| Keywords: | ER stress exosomes fibroblasts macrophages silicosis |