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The neuropeptide CGRP enters the macrophage cytosol to suppress the NLRP3 inflammasome during pulmonary infection

Cellular & Molecular Immunology volume 20, pages 264–276 (2023)Cite this article

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Abstract

The NLRP3 inflammasome plays an essential role in resistance to bacterial infection. The nervous system secretes multiple neuropeptides affecting the nervous system as well as immune cells. The precise impact of the neuropeptide CGRP on NLRP3 inflammasome activation is still unclear. Here, we show that CGRP negatively regulates the antibacterial process of host cells. CGRP prevents NLRP3 inflammasome activation and reduces mature IL-1β secretion. Following NLRP3 inflammasome stimulation that triggers endosome leakage, CGRP internalized to endosomal compartments is released into the cell cytosol. Cytosolic CGRP binds directly to NLRP3 and dismantles the NLRP3-NEK7 complex, which is crucial for NLRP3 inflammasome activation. CGRP administration exacerbates bacterial infection, while the treatment with a CGRP antagonist has the opposite effect. Our study uncovers a unique role of CGRP in inhibiting inflammasome activation during infections, which might shed new light on antibacterial therapies in the future.

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Acknowledgements

We thank Ting Li (Peking University) for technical help. This work was supported by the National Natural Science Foundation of China (81922031, 82271790, 92169113), Beijing Natural Science Foundation (7212067), National Key R&D Program of China (2019YFA0111800, 2022YFC2302900), Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB29020000), Key Research Program of Frontier Sciences of Chinese Academy of Sciences (ZDBS-LY-SM025), CAS Project for Young Scientists in Basic Research (YSBR-010), Fok Ying Tung Education Foundation to PX, and Youth Innovation Promotion Association of CAS to SW.

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Author notes

  1. These authors contributed equally: Fangrui Zhu, Dou Yu, Xiwen Qin, Yan Qian.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Peking University, 100191, Beijing, China

    Fangrui Zhu, Xiwen Qin, Yan Qian, Juan Ma, Weitao Li, Qiannv Liu, Chunlei Wang, Yan Zhang & Pengyan Xia

  2. NHC Key Laboratory of Medical Immunology, Peking University, 100191, Beijing, China

    Fangrui Zhu, Xiwen Qin, Yan Qian, Juan Ma, Weitao Li, Qiannv Liu, Chunlei Wang, Yan Zhang & Pengyan Xia

  3. Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, 100191, Beijing, China

    Fangrui Zhu, Xiwen Qin, Yan Qian, Juan Ma, Weitao Li, Qiannv Liu, Chunlei Wang, Yan Zhang & Pengyan Xia

  4. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China

    Dou Yu & Shuo Wang

  5. Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China

    Dou Yu & Shuo Wang

  6. Department of Anesthesiology, Peking University Third Hospital, 100191, Beijing, China

    Yi Li

  7. Department of Sports Medicine, Peking University Third Hospital, 100191, Beijing, China

    Dong Jiang

  8. Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, 100191, Beijing, China

    Dong Jiang

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Contributions

FZ, DY, and XQ designed and performed experiments and analyzed data; JM, WL, QL, CW, YL, DJ, YZ, YQ, and SW performed the experiments and analyzed the data; SW and PX initiated the study, designed and performed experiments, analyzed data, and wrote the paper.

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Correspondence to Shuo Wang or Pengyan Xia.

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Zhu, F., Yu, D., Qin, X. et al. The neuropeptide CGRP enters the macrophage cytosol to suppress the NLRP3 inflammasome during pulmonary infection. Cell Mol Immunol 20, 264–276 (2023). https://doi.org/10.1038/s41423-022-00968-w

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