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IRF-1 Intervention in the Classical ROS-Dependent Release of NETs during LPS-Induced Acute Lung Injury in Mice

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Abstract

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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Funding

This work was supported by the National Natural Science Foundation of China (nos. 81770080 and 81470266).

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine (Department of Respiratory Medicine), Key cite of National Clincial Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Shuai Liu, Pinhua Pan, Xiaoli Su, Haitao Li, Haosi Li, Yi Li, Minhui Dai, Qian Li & Zhi Mao

  2. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Yinyan Yue

  3. Department of Thoracic Medicine, Hunan Cancer Hospital, Affiliated to Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China

    Lemeng Zhang

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  1. Shuai Liu
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  2. Yinyan Yue
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  3. Pinhua Pan
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  5. Xiaoli Su
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Contributions

S.L. performed the experiments and drafted the manuscript; S.L., Y.Y., Y.L., Z.M., and H.L. analyzed the data; S.L. and X.S. interpreted the experimental results; L.Z. verified the pathological results; S.L., H.L., Q.L., and M.D. prepared the figures; P.P. conceived and designed the research; P.P. and L.Z. edited and revised the manuscript; P.P. approved the final version of manuscript. All authors read and approved the final manuscript.

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Correspondence to Pinhua Pan.

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Liu, S., Yue, Y., Pan, P. et al. IRF-1 Intervention in the Classical ROS-Dependent Release of NETs during LPS-Induced Acute Lung Injury in Mice. Inflammation 42, 387–403 (2019). https://doi.org/10.1007/s10753-018-0903-7

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