ACKR3 agonism induces heterodimerization with chemokine receptor CXCR4 and attenuates platelet function
ACKR3 agonism induces heterodimerization with chemokine receptor CXCR4 and attenuates platelet function
Abstract BackgroundPlatelet receptors ACKR3 and CXCR4 play a crucial role in a variety of cardio-vascular diseases. Like most chemokine receptors, CXCR4 is a G protein coupled receptor that induces platelet activation. In contrast, the atypical chemokine receptor 3 (ACKR3) lacks the ability to activate heterotrimeric G proteins and its activation leads to platelet inhibition and attenuates thrombus formation. In nucleated cells, heterodimerization of ACKR3 with CXCR4 regulates CXCL12-dependent signaling. The aim of our study was to investigate the formation of ACKR3/CXCR4 heterodimers in platelets and the subsequent consequences for platelet function. Methods and resultsUsing a microscopy proximity ligation assay (PLA, Duolink?) to screen for CXCR4/ACKR3 heterodimerization inducing compounds, we found that ACKR3 agonism but not conventional platelet agonists or endogen ligands lead to heterodimer formation. To further characterize the formation of ACKR3/CXCR4 heterodimers, we studied the CXCL12-dependent platelet activation via CXCR4. Both, CXCL12-dependent platelet aggregation and collagen-dependent ex vivo thrombus formation were significantly downregulated by ACKR3 agonism. Moreover, platelet intracellular calcium and Akt signaling were increased by CXCL12 and again suppressed by ACKR3-specific agonists. Previously, CXCL12 was shown to decrease platelet cAMP levels via CXCR4. Treatment with a specific ACKR3 agonist counteracted this CXCL12/CXCR4-dependent cAMP decrease. ConclusionOur results reveal that the formation of platelet ACKR3/CXCR4 heterodimers is dependent on ACKR3 rather than CXCR4. Furthermore, ACKR3 agonism induced heterodimerization is associated with mitigating CXCL12/CXCR4-dependent platelet activation possibly by modulating CXCR4-dependent G protein signaling. Our results indicate possible ACKR3 agonist functions and reinforce the potential therapeutic applications of ACKR3 agonists. biorxiv;2024.05.10.593491v1/UFIG1F1ufig1Graphical abstract:CXCR4/ACKR3 heterodimerization in platelets.
Pillaiyar Thanigaimalai、Rohlfing Anne-Katrin、Schaale David、Bayrak Alp、Sigle Manuel、Laspa Zoi、Castor Tatsiana、Laufer Stefan、Dicenta-Baunach Valerie、Gawaz Meinrad Paul
Institute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University T¨1bingen||T¨1bingen Center for Academic Drug Discovery & Development (T¨1CAD2), Eberhard Karls University T¨1bingenDepartment of Cardiology and Angiology, University Hospital T¨1bingen, Eberhard Karls University T¨1bingenDepartment of Cardiology and Angiology, University Hospital T¨1bingen, Eberhard Karls University T¨1bingenInstitute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University T¨1bingenDepartment of Cardiology and Angiology, University Hospital T¨1bingen, Eberhard Karls University T¨1bingenDepartment of Cardiology and Angiology, University Hospital T¨1bingen, Eberhard Karls University T¨1bingenDepartment of Cardiology and Angiology, University Hospital T¨1bingen, Eberhard Karls University T¨1bingenInstitute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University T¨1bingen||T¨1bingen Center for Academic Drug Discovery & Development (T¨1CAD2), Eberhard Karls University T¨1bingen||iFIT Cluster of Excellence EXC 2180 ??Image-Guided and Functionally Instructed Tumor Therapies?ˉ, Eberhard Karls University T¨1bingenDepartment of Cardiology and Angiology, University Hospital T¨1bingen, Eberhard Karls University T¨1bingenDepartment of Cardiology and Angiology, University Hospital T¨1bingen, Eberhard Karls University T¨1bingen
基础医学生理学分子生物学
Pillaiyar Thanigaimalai,Rohlfing Anne-Katrin,Schaale David,Bayrak Alp,Sigle Manuel,Laspa Zoi,Castor Tatsiana,Laufer Stefan,Dicenta-Baunach Valerie,Gawaz Meinrad Paul.ACKR3 agonism induces heterodimerization with chemokine receptor CXCR4 and attenuates platelet function[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2024.05.10.593491.点此复制
评论