Journal
INFLAMMATION
Volume 42, Issue 1, Pages 387-403Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10753-018-0903-7
Keywords
acute lung injury; interferon regulatory factor-1; neutrophil extracellular traps; reactive oxygen species; lipopolysaccharide
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Funding
- National Natural Science Foundation of China [81770080, 81470266]
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Previously, we demonstrated that neutrophil extracellular traps (NETs) play an essential role in lipopolysaccharide (LPS)-induced acute lung injury. However, the underlying mechanism is unclear. In this study, we showed that knockout of interferon regulatory factor 1 (IRF-1) in mice strongly attenuated the generation of NETs and reactive oxygen species (ROS) production in neutrophils from bronchoalveolar lavage fluid and alleviated LPS-induced lung injury and systemic inflammation. Our in vitro experiments demonstrated that LPS-stimulated platelets induce NET release through two distinct processes: an ROS-independent early/rapid NETosis and a later ROS-dependent classical NETosis. Notably, the classical ROS-dependent pathway plays a dominant role in the generation of NETs. Furthermore, we showed that IRF-1 knockout does not affect the formation of NETs in early/rapid NETosis, but significantly attenuates ROS production and the generation of NETs in classical NETosis, which determines the total levels of NETs released by LPS-stimulated platelets. In conclusion, IRF-1 deficiency plays a key role in moderating the excessive NETs formed via ROS in the classical pathway and retaining the protective role of the low-NET levels generated in early/rapid NETosis, which may serve as a novel target in acute lung injury/acute respiratory distress syndrome.
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