期刊
CHEMOSPHERE
卷 307, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.chemosphere.2022.135794
关键词
PM2.5; Pulmonary fibrosis; Inflammasomes; PP2A; IRE1 alpha
资金
- National Natural Science Foundation of China [92043202, 81973074, 91643108, 81573190, 91943301]
This study identified the key signaling pathways involved in PM2.5-induced pulmonary fibrosis, including PP2A-IRE1α-NLRP3 pathway. PM2.5 exposure led to lung inflammation and fibrosis, and PP2A was found to play an important role in regulating pulmonary injury.
Ambient particulate matter 2.5 (PM2.5) exposure has been linked to pulmonary fibrosis. However, the key signaling pathways remained unclear. In the present study, we applied a mouse model with myeloid-specific deletion of Ppp2r1a gene (encoding protein phosphatase 2 A (PP2A) A subunit) to identify the key signaling pathways involved in PM2.5-induced pulmonary fibrosis. PP2A A alpha(-/-) homozygote mice and matched wild-type (WT) littermates were exposed to filtered air (FA), unfiltered air (UA), and concentrated PM2.5 (CA) in a real-ambient PM exposure system for 8 weeks and 16 weeks, respectively. The mice exposed to PM2.5 displayed a progressive inflammation and pulmonary fibrosis. Moreover, the expressions of NLRP3, pro-caspase-1, caspase-1, ASC and IL-1 beta were increased in mice lung following PM2.5 exposure, indicating PM2.5 exposure caused pulmonary inflammation by the NLRP3 pathways activation. Furthermore, the effects of PM exposure on pulmonary inflammation, pulmonary fibrosis, oxidative stress, and pulmonary function damage were significantly enhanced in PP2A(-/-) mice compared to WT mice, indicating the role of PP2A in the regulation of pulmonary injury induced by PM exposure. In vitro study confirmed that PP2A was involved in the PM2.5-induced inflammation response and NLRP3 inflammasome activation. Importantly, we identified PP2A regulated the activation of NLRP3 pathways by direct dephosphorylating IRE1 alpha in response to PM2.5 exposure. Taken together, our results demonstrated that PP2A-IRE1 alpha-NLRP3 signaling pathway played a crucial role in regulating the inflammation response, triggering the lung fibrogenesis upon PM2.5 exposure. Our findings provide new insights into regulatory role of PP2A in human diseases upon the PM exposure.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据