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 Antonelou, Scott R. Henderson, Alan Salama, Elena Seiradake () and Hsi-Hsien Lin ()
Additional contact information
Tai-Ying Chu: Chang Gung University
Céline Zheng-Gérard: University of Oxford
Kuan-Yeh Huang: Chang Gung University
Yu-Chi Chang: Chang Gung University
Ying-Wen Chen: Chang Gung University
Kuan-Yu I: Chang Gung University
Yu-Ling Lo: Chang Gung University
Nien-Yi Chiang: Chang Gung University
Hsin-Yi Chen: Chang Gung University
Martin Stacey: University of Leeds
Siamon Gordon: Chang Gung University
Wen-Yi Tseng: Chang Gung Memorial Hospital-Keelung
Chiao-Yin Sun: Chang Gung Memorial Hospital-Keelung
Yen-Mu Wu: Chang Gung University
Yi-Shin Pan: Chang Gung Memorial Hospital-Linkou
Chien-Hao Huang: Chang Gung Memorial Hospital-Linkou
Chun-Yen Lin: Chang Gung Memorial Hospital-Linkou
Tse-Ching Chen: Chang Gung Memorial Hospital-Linkou
Kamel El Omari: Diamond Light Source Limited, Harwell Science and Innovation Campus
Marilina Antonelou: Royal Free Campus, UCL
Scott R. Henderson: Royal Free Campus, UCL
Alan Salama: Royal Free Campus, UCL
Elena Seiradake: University of Oxford
Hsi-Hsien Lin: Chang Gung University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34083-1

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