Divalent cation-dependent and -independent augmentation of macrophage phagocytosis of apoptotic neutrophils by CD44 antibody

Abstract

Phagocytosis of apoptotic neutrophils by macrophages is required for resolution of an inflammatory response. Removal of intact apoptotic neutrophils prevents the release of cytotoxic granules that would otherwise cause tissue damage and may lead to development of fibrosis. Importantly, macrophage phagocytosis of apoptotic neutrophils fails to induce release of proinflammatory mediators, consistent with a 'safe' pathway for disposal of potentially harmful inflammatory cells. One pathway for increasing phagocytosis of apoptotic cells to allow matching of tissue phagocyte capacity to apoptotic cell load in vitro is via antibody-mediated cross-linking of CD44, providing a mechanism for limiting tissue damage during resolution of inflammation. In this study, we have defined divalent cation-dependent and -independent actions of the CD44 antibody. For the divalent cation-independent CD44 antibody effect, we provide evidence that 'enabled' CD32 on the apoptotic neutrophil binds to intact CD44 antibody on the macrophage surface. One implication is that macrophages can phagocytose apoptotic neutrophils that are 'tethered' to the macrophage surface in a manner that is independent of defined apoptotic mechanisms. These data also provide an explanation for the greater efficacy of intact CD44 antibody when compared with F(ab')2 fragments.