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

Fangrui Zhu; Dou Yu; Xiwen Qin; Yan Qian; Juan Ma; Weitao Li; Qiannv Liu; Chunlei Wang; Yan Zhang; Yi Li; Dong Jiang; Shuo Wang; Pengyan Xia

doi:10.1038/s41423-022-00968-w

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

Cell Mol Immunol. 2023 Mar;20(3):264-276. doi: 10.1038/s41423-022-00968-w. Epub 2023 Jan 5.

Authors

Fangrui Zhu^#^{1

2

3}, Dou Yu^#^{4

5}, Xiwen Qin^#^{1

2

3}, Yan Qian^#^{1

2

3}, Juan Ma^{1

2

3}, Weitao Li^{1

2

3}, Qiannv Liu^{1

2

3}, Chunlei Wang^{1

2

3}, Yan Zhang^{1

2

3}, Yi Li⁶, Dong Jiang^{7

8}, Shuo Wang^{9

10}, Pengyan Xia^{11

12

13}

Affiliations

¹ Department of Immunology, School of Basic Medical Sciences, Peking University, 100191, Beijing, China.
² NHC Key Laboratory of Medical Immunology, Peking University, 100191, Beijing, China.
³ Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, 100191, Beijing, China.
⁴ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China.
⁵ Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
⁶ Department of Anesthesiology, Peking University Third Hospital, 100191, Beijing, China.
⁷ Department of Sports Medicine, Peking University Third Hospital, 100191, Beijing, China.
⁸ Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, 100191, Beijing, China.
⁹ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China. wangshuo@im.ac.cn.
¹⁰ Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China. wangshuo@im.ac.cn.
¹¹ Department of Immunology, School of Basic Medical Sciences, Peking University, 100191, Beijing, China. xiap@pku.edu.cn.
¹² NHC Key Laboratory of Medical Immunology, Peking University, 100191, Beijing, China. xiap@pku.edu.cn.
¹³ Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, 100191, Beijing, China. xiap@pku.edu.cn.

^# Contributed equally.

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.

Keywords: CGRP; Inflammasome; NLRP3; Neuropeptide; Suppressor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcitonin Gene-Related Peptide / metabolism
Cytosol / metabolism
Inflammasomes* / metabolism
Interleukin-1beta / metabolism
Macrophages
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Calcitonin Gene-Related Peptide
Interleukin-1beta