Platelet Factor 4/CXCL4 Induces Phagocytosis and the Generation of Reactive Oxygen Metabolites in Mononuclear Phagocytes Independently of Gi Protein Activation or Intracellular Calcium Transients

• DOI: 10.4049/jimmunol.173.3.2060
• Publication Date: 2014-04-23T03:38:25Z
• Authors: Olga Pervushina; Barbara Scheuerer; Norbert Reiling; Lars Behnke; Jens.-M. Schröder; Brigitte Kasper; Ernst Brandt; Silvia Bulfone-Paus; Frank Petersen
• Keywords: 0301 basic medicine; Receptors, CXCR3; Macrophages; Cell Differentiation; Drug Synergism; GTP-Binding Protein alpha Subunits, Gi-Go; Macrophage Activation; Platelet Factor 4; Monocytes; Mice, Inbred C57BL; N-Formylmethionine Leucyl-Phenylalanine; Mice; 03 medical and health sciences; Phagocytosis; Animals; Humans; Receptors, Chemokine; Calcium Signaling; Reactive Oxygen Species; Chemokine CCL5; Cells, Cultured; Respiratory Burst

Abstract Platelet factor 4 (PF-4), a platelet-derived CXC chemokine, is known to prevent human monocytes from apoptosis and to promote differentiation of these cells into HLA-DR− macrophages. In this study, we investigated the role of PF-4 in the control of acute monocyte proinflammatory responses involved in the direct combat of microbial invaders. We show that PF-4 increases monocyte phagocytosis and provokes a strong formation of oxygen radicals but lacks a chemotactic activity in these cells. Compared with FMLP, PF-4-induced oxidative burst was later in its onset but was remarkably longer in its duration (lasting for up to 60 min). Furthermore, in PF-4-prestimulated cells, FMLP- as well as RANTES-induced burst responses became synergistically enhanced. As we could show, PF-4-mediated oxidative burst in monocytes does not involve Gi proteins, elevation of intracellular free calcium concentrations, or binding to CXCR3B, a novel PF-4 receptor recently discovered on endothelial cells. Moreover, we found that PF-4 acts on macrophages in a dual manner. On the one hand, very similar to GM-CSF or M-CSF, PF-4 treatment of monocytes generates macrophages with a high capacity for unspecific phagocytosis. On the other hand, short term priming of GM-CSF-induced human macrophages with PF-4 substantially increases their capability for particle ingestion and oxidative burst. A comparable effect was also observed in murine bone marrow-derived macrophages, indicating cross-reactivity of human PF-4 between both species. Taken together, PF-4 may play a crucial role in the induction and maintenance of an unspecific immune response.