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Cited by 37Neutrophil, Myeloperoxidase and Oxidative MechanismsInflammation biomarkers and pathwaysBlood Coagulation and Thrombosis Mechanisms

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GPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation

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Chu, Tai-Ying, Zheng-Gérard, Céline, Huang, Kuan-Yeh, Chang, Yu-Chi, Chen, Ying-Wen, I, Kuan-Yu, Lo, Yu-Ling, Chiang, Nien-Yi, Chen, Hsin-Yi, Stacey, Martin, Gordon, Siamon, Tseng, Wen-Yi, Sun, Chiao-Yin, Wu, Yen-Mu, Pan, Yi-Shin, Huang, Chien-Hao, Lin, Chun-Yen, Chen, Tse-Ching, El Omari, Kamel, Antonelou, Marilina, Henderson, Scott R., Salama, Alan, Seiradake, Elena, Lin, Hsi-Hsien·2022·Nature Communications
DOI 10.1038/s41467-022-34083-1PMC PMC9613636

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Abstract

Neutrophils play essential anti-microbial and inflammatory roles in host defense, however, their activities require tight regulation as dysfunction often leads to detrimental inflammatory and autoimmune diseases. Here we show that the adhesion molecule GPR97 allosterically activates CD177-associated membrane proteinase 3 (mPR3), and in conjugation with several protein interaction partners leads to neutrophil activation in humans. Crystallographic and deletion analysis of the GPR97 extracellular region identified two independent mPR3-binding domains. Mechanistically, the efficient binding and activation of mPR3 by GPR97 requires the macromolecular CD177/GPR97/PAR2/CD16b complex and induces the activation of PAR2, a G protein-coupled receptor known for its function in inflammation. Triggering PAR2 by the upstream complex leads to strong inflammatory activation, prompting anti-microbial activities and endothelial dysfunction. The role of the complex in pathologic inflammation is underscored by the finding that both GPR97 and mPR3 are upregulated on the surface of disease-associated neutrophils. In summary, we identify a PAR2 activation mechanism that directs neutrophil activation, and thus inflammation. The PR3/CD177/GPR97/PAR2/CD16b protein complex, therefore, represents a potential therapeutic target for neutrophil-mediated inflammatory diseases.

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Metadata

Authors
Chu, T.-Y., Zheng-Gérard, C., Huang, K.-Y., Chang, Y.-C., Chen, Y.-W., I, K.-Y., Lo, Y.-L., Chiang, N.-Y., Chen, H.-Y., Stacey, M., Gordon, S., Tseng, W.-Y., Sun, C.-Y., Wu, Y.-M., Pan, Y.-S., Huang, C.-H., Lin, C.-Y., Chen, T.-C., El Omari, K., Antonelou, M., Henderson, S. R., Salama, A., Seiradake, E., & Lin, H.-H.
Affiliations
  • Chang Gung University (TW)
  • University of Leeds (GB)
  • Chang Gung Memorial Hospital (TW)
  • The Royal Free Hospital (GB)
  • University of Oxford (GB)
Corresponding author
  • Seiradake, Elena
  • Lin, Hsi-Hsien
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-10-27
Volume
13
Issue
1
Pages
6385-6385
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34083-1
PMC
PMC9613636
OpenAlex
W4307838309
Cited by
37
References
2
Citations by year
2026: 10 · 2025: 7 · 2024: 14 · 2023: 6
FWCI
2.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust (202827/Z/16/Z, 202827)
  • Chang Gung University
  • Chang Gung Medical Foundation
  • Ministry of Science and Technology, Taiwan (MOST107-2320-B182-006-MY3, MOST110-2320-B182-024-MY3)
  • Medical Research Council (MR/L018039/1)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords
neutrophil activation, PAR2, CD177, CD16b, inflammation, antimicrobial activity, endothelial dysfunction, therapeutic target
MeSH terms
Humans, Inflammation, Neutrophils, Phagocytosis, Neutrophil Activation, Receptors, G-Protein-Coupled, Receptor, PAR-2, Myeloblastin

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