Interaction of platelet-derived inflammatory mediators and their receptors CXCR4 and CXCR7 regulating platelet function and inflammation

• Applicant: Professor Dr. Meinrad Paul Gawaz
• Subject Area: Cardiology, Angiology
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190538538

Final Report Abstract

We explored the role of inflammatory mediators and their cognate receptors CXCR4-CXCR7 in regulating thrombotic and thromboinflammatory attributes of platelets. To briefly summarize our investigation and research output we highlight the following: We established CXCR4 and CXCR7 on platelets as functional receptors for several chemokines like CXCL11, CXCL12, CXCL14 and the chemokine like cytokine macrophage migration inhibitory factor (MIF). CXCR4 and CXCR7 are preferentially engaged by these ligands and differentially regulate platelet survival and pro/anti-thrombotic response and their thromboinflammatory interaction with inflammatory cells like monocytes. - We characterized the impact and relative significance of the genetic deletion of CXCR4 and CXCR7 from megakaryocyte-platelet lineage in governing platelet responsiveness under basal conditions and following myocardial infarction (MI) and cerebral stroke. - We identified platelets as a novel source of the chemokine CXCL14 and Gremlin-1, a functional antagonist of MIF, both of which can regulate thrombotic and thromboinflammatory platelet functions. - We demonstrated the clinical significance of platelet CXCR4-CXCR7 in the context of coronary artery disease (CAD), established the prognostic significance of these receptors on platelets along with other platelet based biomarkers like CXCL14 and circulatory biomarkers like MIF and Gremlin-1.

Publications

• Macrophage migration inhibitory factor is enhanced in acute coronary syndromes and is associated with the inflammatory response. PLoS One. 2012;7:e38376
  Müller II, Müller KA, Schönleber H, Karathanos A, Schneider M, Jorbenadze R, Bigalke B, Gawaz M, Geisler T
  
• Gremlin-1 is an inhibitor of macrophage migration inhibitory factor and attenuates atherosclerotic plaque growth in ApoE-/- Mice. J Biol Chem. 2013; 288:31635-45
  Müller I, Schönberger T, Schneider M, Borst O, Ziegler M, Seizer P, Leder C, Müller K, Lang M, Appenzeller F, Lunov O, Büchele B, Fahrleitner M, Olbrich M, Langer H, Geisler T, Lang F, Chatterjee M, de Boer JF, Tietge UJ, Bernhagen J, Simmet T, Gawaz M
  
• Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. Eur Heart J. 2014; 35:386-94
  Rath D, Chatterjee M, Borst O, Müller K, Stellos K, Mack AF, Bongartz A, Bigalke B, Langer H, Schwab M, Gawaz M, Geisler T
  
• Macrophage migration inhibitory factor limits activation-induced apoptosis of platelets via CXCR7-dependent Akt signaling. Circ Res. 2014; 115:939-49
  Chatterjee M, Borst O, Walker B, Fotinos A, Vogel S, Seizer P, Mack A, Alampour-Rajabi S, Rath D, Geisler T, Lang F, Langer HF, Bernhagen J, Gawaz M
  
• SDF-1α induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival. FASEB J. 2014; 28:2864-78
  Chatterjee M, Seizer P, Borst O, Schönberger T, Mack A, Geisler T, Langer HF, May AE, Vogel S, Lang F, Gawaz M
  
• Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. Cell Death Dis. 2015; 19: 6:e1989
  Chatterjee M, von Ungern-Sternberg S, Seizer P, Schlegel F, Büttcher M, Sindhu NA, Müller S, Mack A, Gawaz M
  
• Platelets as a novel source of Gremlin-1: Implications for thromboinflammation. Thromb Haemost. 2017;117:311-324
  Chatterjee M, Behrendt A, Schmid M, Beck S, Schneider M, Mack A, Müller I, Geisler T, Gawaz M
  
• Platelets as a novel source of pro-inflammatory chemokine CXCL14. Cell Physiol Biochem. 2017; 41:1684-1696
  Witte A, Chatterjee M, Lang F, Gawaz M
  
• Regulation of oxidized platelet lipidome: implications for coronary artery disease. Eur Heart J. 2017; 38:1993-2005
  Chatterjee M, Rath D, Schlotterbeck J, Rheinlaender J, Walker-Allgaier B, Alnaggar N, Zdanyte M, Müller I, Borst O, Geisler T, Schäffer TE, Lämmerhofer M, Gawaz M