Serum‐derived exosomes from SD rats induce inflammation in macrophages through the mTOR pathway

• Published in: Journal of applied toxicology Vol. 42; no. 9; pp. 1524 - 1532
• Main Authors: Wang, Ye, Liu, Yan‐ping, Sun, Zhan‐bing, Deng, Wei‐hua, Yuan, Xiao‐yan, Lei, Yuan‐di, Cai, Ying, Huang, Lian, Zhang, Zhao‐hui
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2022
• Subjects: Animals; Beryllium; Beryllium - pharmacology; Beryllium - toxicity; Beryllium compounds; beryllium sulfate; Biocompatibility; Cytokines; Endosomes; Exosomes; Exosomes - metabolism; Inflammation; Inflammation - chemically induced; Inhalation; Interferon; lung injury; Lungs; Macrophages; Membrane vesicles; Mice; mTOR pathway; Nitric-oxide synthase; Oxidative stress; Rapamycin; Rats; Rats, Sprague-Dawley; Respiration; Rodents; Signal transduction; Sirolimus - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Toxicity; Trachea; Tumor necrosis factor; mTOR pathway; lung injury; beryllium sulfate; inflammation; exosomes
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.4321

Inhalation of beryllium and its compounds can cause lung injuries, resulting from inflammation and oxidative stress. Multivesicular bodies (MVB), such as exosomes, are membrane vesicles produced by early and late endosomes that mediate intercellular communications. However, the role of exosomes in beryllium toxicity has not been elucidated. This current study aimed to investigate the functional role of exosomes in lung injury resulting from beryllium sulfate (BeSO4). Here, Sprague–Dawley (SD) rats were exposed to 4, 8, and 12 mg/kg BeSO4 by nonexposed intratracheal instillation. Murine macrophage (RAW 264.7) cells were pretreated with 50 nmol/L rapamycin (an mTOR signaling pathway inhibitor) for 30 min and then cultured for 24 h with 100 μg/mL exosomes, which had been previously isolated from the serum of 12 mg/kg BeSO4‐treated SD rats. Compared with those of the controls, exposure to BeSO4 in vivo increased LDH activity, elevated levels of inflammatory cytokines (IL‐10, TNF‐α, and IFN‐γ) alongside inflammation‐related proteins expression (COX‐2 and iNOS), and enhanced secretion of exosomes from the SD rat's serum. Moreover, the BeSO4‐Exos‐induced upregulation of LDH activity and inflammatory responses in RAW 264.7 cells can be alleviated following pretreatment with rapamycin. Collectively, these results suggest that serum exosomes play an important role in pulmonary inflammation induced by BeSO4 in RAW 264.7 cells via the mTOR pathway. Beryllium sulfate (BeSO4) can cause inflammation of the lung. Exosomes mediate intercellular communications. This study aimed to investigate the role of exosomes in BeSO4‐induced lung injury. BeSO4 increased the level of LDH, inflammation‐related cytokines and proteins, and the secretion of serum‐derived exosomes in SD rats. The BeSO4‐Exos‐induced upregulation of LDH and inflammatory responses in macrophages can be alleviated by rapamycin pretreatment. It concluded that serum exosomes are essential in BeSO4‐induced inflammation in macrophages via the mTOR pathway.