The neuropeptide cgrp enters the macrophage cytosol to suppress the nlrp3 inflammasome during pulmonary infection

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. Access through your institution Buy or subscribe This is a preview of subscription content,

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MACROPHAGES IS DEPENDENT ON NLRP3, RIG-I, AND TLR3 Article Open access 11 December 2022 MAFB REGULATES NLRP3 INFLAMMASOME ACTIVATION BY SUSTAINING P62 EXPRESSION IN MACROPHAGES Article Open

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Article  CAS  PubMed  PubMed Central  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * These

authors contributed equally: Fangrui Zhu, Dou Yu, Xiwen Qin, Yan Qian. AUTHORS AND AFFILIATIONS * 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 * 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 * 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 * CAS Key Laboratory of Pathogen

Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China Dou Yu & Shuo Wang * Center for Biosafety Mega-Science, Chinese Academy of

Sciences, Wuhan, Hubei, 430071, China Dou Yu & Shuo Wang * Department of Anesthesiology, Peking University Third Hospital, 100191, Beijing, China Yi Li * Department of Sports Medicine,

Peking University Third Hospital, 100191, Beijing, China Dong Jiang * Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, 100191, Beijing, China

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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. CORRESPONDING AUTHORS Correspondence to Shuo Wang or Pengyan Xia. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 27 August 2022 * Accepted: 11 December 2022 * Published:

05 January 2023 * Issue Date: March 2023 * DOI: https://doi.org/10.1038/s41423-022-00968-w SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

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Neuropeptide * CGRP * NLRP3 * Inflammasome * Suppressor