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

Tai Ying Chu, Céline Zheng-Gérard, Kuan Yeh Huang, Yu Chi Chang, Ying Wen Chen, Kuan Yu I, Yu Ling Lo, Nien Yi Chiang, Hsin Yi Chen, Martin Stacey, Siamon Gordon, Wen Yi Tseng, Chiao Yin Sun, Yen Mu Wu, Yi Shin Pan, Chien Hao Huang, Chun Yen Lin, Tse-Ching Chen, Kamel El Omari, Marilina AntonelouScott R. Henderson, Alan Salama, Elena Seiradake*, Hsi Hsien Lin*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations

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.

Original languageEnglish
Article number6385
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - 12 2022

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