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Publication Detail
GPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation
  • Publication Type:
    Journal article
  • Authors:
    Chu TY, Zheng-Gérard C, Huang KY, Chang YC, Chen YW, I KY, Lo YL, Chiang NY, Chen HY, Stacey M, Gordon S, Tseng WY, Sun CY, Wu YM, Pan YS, Huang CH, Lin CY, Chen TC, El Omari K, Antonelou M, Henderson SR, Salama A, Seiradake E, Lin HH
  • Publisher:
    Springer Science and Business Media LLC
  • Publication date:
    27/10/2022
  • Journal:
    Nature Communications
  • Volume:
    13
  • Article number:
    6385
  • Medium:
    Electronic
  • Status:
    Published
  • Country:
    England
  • Print ISSN:
    2041-1723
  • PII:
    10.1038/s41467-022-34083-1
  • Language:
    English
  • Keywords:
    Cell signalling, G protein-coupled receptors, Inflammation, Neutrophils
  • Notes:
    This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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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