REGULATION OF MACROPHAGE PHAGOCYTOSIS OF APOPTOTIC NEUTROPHILS BY ADHESION TO FIBRONECTIN

The potential for leukocyte-mediated host tissue damage during resolut ion of inflammatory responses is influenced by the rate at which extra vasated apoptotic leukocytes are cleared from inflammatory sites. Regu lation of macrophage capacity for clearance of apoptotic granulocytes is likely to be an important factor determining whether inflammation u ltimately resolves or progresses to a chronic state. In this study we have investigated the molecular basis for rapid augmentation of macrop hage phagocytosis of apoptotic neutrophils, which was observed followi ng macrophage adhesion to fibronectin. We used a combination of monocl onal antibodies, blocking peptides, and recombinant fibronectin fragme nts to investigate the role of beta(1) integrins in mediating the fibr onectin effects. Blockade of alpha(5)beta(1) or alpha(4)beta(1) alone did not attenuate fibronectin-augmentation of phagocytosis. In additio n, adhesion of macrophages to recombinant fibronectins lacking alpha(4 )beta(1) recognition motifs failed to promote phagocytosis of apoptoti c neutrophils. Our results would be consistent with a model in which m ultiple fibronectin receptors, including beta(1) integrins, act co-ope ratively to augment macrophage phagocytic responses. Together; these d ata suggest that the extracellular matrix environment of macrophages m ay provide regulatory signals that act indirectly to rapidly alter the potential for removal of apoptotic cells and influence the process of resolution of inflammation.