Abstract
Platelets store and release CXCL12 (SDF-1), which governs differentiation of hematopoietic progenitors into either endothelial or macrophage-foam cells. CXCL12 ligates CXCR4 and CXCR7 and regulates monocyte/macrophage functions. This study deciphers the relative contribution of CXCR4–CXCR7 in mediating the effects of platelet-derived CXCL12 on monocyte function, survival, and differentiation. CXCL12 and macrophage migration inhibitory factor (MIF) that ligate CXCR4–CXCR7 induced a dynamic bidirectional trafficking of the receptors, causing CXCR4 internalization and CXCR7 externalization during chemotaxis, thereby influencing relative receptor availability, unlike MCP-1. In vivo we found enhanced accumulation of platelets and platelet-macrophage co-aggregates in peritoneal fluid following induction of peritonitis in mice. The relative surface expression of CXCL12, CXCR4, and CXCR7 among infiltrated monocytes was also enhanced as compared with peripheral blood. Platelet-derived CXCL12 from collagen-adherent platelets and recombinant CXCL12 induced monocyte chemotaxis specifically through CXCR4 engagement. Adhesion of monocytes to immobilized CXCL12 and CXCL12-enriched activated platelet surface under static and dynamic arterial flow conditions were mediated primarily through CXCR7 and were counter-regulated by neutralizing platelet-derived CXCL12. Monocytes and culture-derived-M1–M2 macrophages phagocytosed platelets, with the phagocytic potential of culture-derived-M1 macrophages higher than M2 involving CXCR4–CXCR7 participation. CXCR7 was the primary receptor in promoting monocyte survival as exerted by platelet-derived CXCL12 against BH3-mimetic induced apoptosis (phosphatidylserine exposure, caspase-3 activation, loss of mitochondrial transmembrane potential). In co-culture experiments with platelets, monocytes predominantly differentiated into CD163+ macrophages, which was attenuated upon CXCL12 neutralization and CXCR4/CXCR7 blocking antibodies. Moreover, OxLDL uptake by platelets induced platelet apoptosis, like other platelet agonists TRAP and collagen-related peptide (CRP). CXCL12 facilitated phagocytosis of apoptotic platelets by monocytes and M1–M2 macrophages, also promoted their differentiation into foam cells via CXCR4 and CXCR7. Thus, platelet-derived CXCL12 could regulate monocyte-macrophage functions through differential engagement of CXCR4 and CXCR7, indicating an important role in inflammation at site of platelet accumulation.
Highlights
Platelets have been recognized to store substantial amounts of CXCL12 in their alpha-granules and release the chemokine upon activation.[5,6] Platelet-derived
Surface expression of CXCR4 and CXCR7 is dynamically regulated on migrating monocytes
The major findings of the present study are (i) surface expression of CXCR4–CXCR7 is dynamically regulated on migrating monocytes, (ii) CXCR4 but not CXCR7 mediates platelet–CXCL12-dependent monocyte migration, (iii) CXCR7 primarily mediates monocyte adhesion to platelet-derived CXCL12, (iv) CXCL12 promotes phagocytosis of platelets by monocytes and macrophages through both CXCR4 and CXCR7, (v) platelet-derived CXCL12 promotes survival of monocytes against BH3-mimetic-induced apoptosis through CXCR7, (vi) platelets induce differentiation of monocytes primarily into CD163+ macrophages through both CXCR4 and CXCR7, and (vii) OxLDL uptake induces platelets apoptosis and facilitates their phagocytic clearance by monocytes, M1–M2 macrophages prompting their subsequent differentiation into lipid-laden foam cells supported by CXCL12–CXCR7
Summary
Platelets have been recognized to store substantial amounts of CXCL12 in their alpha-granules and release the chemokine upon activation.[5,6] Platelet-derived. CXCL12 propagates migration and subsequent differentiation of CD34+ progenitor cells[5,12] into either an endothelial or a macrophage/foam cell phenotype depending on the culture conditions.[12,13] Release of CXCL12 from platelets is enhanced in acute coronary syndromes and correlates with the number of circulating CD34+ progenitor cells and platelet/CD34+ co-aggregates.[14,15] Enhanced levels of platelet–CXCL12 are associated with preservation of left ventricular function following myocardial infarction in humans.[16] Monocytes express both CXCR4 and CXCR7 their role in monocyte function is still incompletely understood.[9,19]. We found that both chemokine receptors have a decisive but differential role for platelet-dependent monocyte function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
