In summary, we identify a PAR2 activation mechanism that directs neutrophil activation, and thus inflammation. 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. Triggering PAR2 by the upstream complex leads to strong inflammatory activation, prompting anti-microbial activities and endothelial dysfunction.
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. Crystallographic and deletion analysis of the GPR97 extracellular region identified two independent mPR3-binding domains. 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. 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. Nature Communications volume 13, Article number: 6385 ( 2022) GPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation
0 kommentar(er)
