CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation

The macrophage fusion receptor (MFR), also called P84/BIT/SIRP alpha /SHPS- 1, is a transmembrane glycoprotein that belongs to the superfamily of immun oglobulins. Previously, we showed that MFR expression is highly induced at the onset of fusion in macrophages, and that MFR appears to play a role in macrophage-macrophage adhesion/fusion leading to multinucleation. The recen t finding that I4P/CD47 acts as a ligand for MFR led us to hypothesize that it interacts with CD47 at the onset of cell-cell fusion. CD47 is a transme mbrane glycoprotein, which, like MFR, belongs to the superfamily of immunog lobulins. We show that macrophages express the hemopoietic form of CD47, th e expression of which is induced at the onset of fusion, but to a lower lev el than MFR. A glutathione S-transferase CD47 fusion protein engineered to contain the extracellular domain of CD47, binds macrophages, associates wit h MFR, and prevents multinucleation. CD47 and MFR associate via their amino -terminal immunoglobulin variable domain. Of the nine monoclonal antibodies raised against the extracellular domain of CD47, three block fusion, as we ll as MFR-CD47 interaction, whereas the others have no effect. Together, th ese data suggest that CD47 is involved in macrophage multinucleation by vir tue of interacting with MFR during adhesion/fusion.