Impact of the CXCR4/ACKR3 axis on platelet activation and thrombo-inflammation

• Applicant: Dr. Anne-Katrin Rohlfing
• Subject Area: Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552766849

We aim to further define the impact of the CXCR4/ACKR3 axis on platelet activation pathways, subpopulation generation and apoptosis. Furthermore, we will investigate their combined roles in I/R injuries and the microenvironment of thromboinflammation. Based on our preliminary work we postulated following working hypotheses. ACKR3 regulates platelet activation, degranulation and aggregation as well as platelet apoptosis and PMV generation. Heterodimerization of ACKR3 with CXCR4 is an important part of this modulatory effect. ACKR3 loss-of-function leads to platelet hyperreactivity, while unregulated CXCR4 activity contributes to this hyperreactivity. ACKR3 has an CXCR4-independent inhibitory effect on platelet activation. To proof our hypotheses, we will use a combination of classical platelet methods, such as aggregometry, and tissue staining approaches combined with modern multi-colour flow cytometer, ImageStream analysis, mass spectrometer and RAMAN microscopy of tissue samples. An established multi-omics approach will be used to integrate the gained data set to form a general survey of all CXCR4/ACKR3 mediated effects. Our newly developed ACKR3 agonist will be applied and tested in vivo and in vitro. The project will give a new understanding of the molecular mechanisms within platelets as well as their function in thromboinflammation. This knowledge will help to develop novel treatment options.

• DFG Programme: Research Grants