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Extracellular histones promote TWIK2-dependent potassium efflux and associated NLRP3 activation in alveolar macrophages during sepsis-induced lung injury

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Abstract

Background and aim

Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux.

Methods and results

We conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane.

Conclusion

These findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis.

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Data availability

The data support the results of the present study are available from the corresponding author upon a reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82170107, to ZMW), the Program of Shanghai Municipal Health Commission (202140406, to ZMW), the Excellent Subject Leader Program of Shanghai Municipal Health Commission (2022XD007, to ZMW), and the Foundation of the Science and Technology Commission of Shanghai Municipality (19ZR1443000 and 23ZR1453300, to ZMW).

Funding

National Natural Science Foundation of China,82170107, Program of Shanghai Municipal Health Commission, 202140406, Foundation of the Science and Technology Commission of Shanghai Municipality,19ZR1443000, 23ZR1453300, Excellent Subject Leader Program of Shanghai Municipal Health Commission, 2022XD007.

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  1. Jing Yu, Yu Fu, and Nan Zhang contributed equally to this work.

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  1. Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Jing Yu, Yu Fu, Nan Zhang, Jiameng Gao, Zhiyuan Zhang, Xuemei Jiang & Zongmei Wen

  2. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Chang Chen

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ZMW secured the funding to support the project and the overall study. ZMW and CC conceptualized, designed, and supervised the study. JY, YF and NZ conducted the experiments, analyzed the results, and contributed to the manuscript writing. JMG, ZYZ and XMJ assisted in performing the experiments and provided technical support. ZMW and CC reviewed and revised the manuscript. All authors reviewed and approved the final version of the manuscript.

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Yu, J., Fu, Y., Zhang, N. et al. Extracellular histones promote TWIK2-dependent potassium efflux and associated NLRP3 activation in alveolar macrophages during sepsis-induced lung injury. Inflamm. Res. (2024). https://doi.org/10.1007/s00011-024-01888-3

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