Macrophage-induced neutrophil apoptosis

Macrophages (M phi) contribute to the resolution of early inflammation by recognizing and ingesting apoptotic polymorphonuclear neutrophils (PMN). In addition, experiments reported here demonstrated that M phi can actively induce PMN apoptosis, Coculture of cells from 2- or 5-day-old wounds in rats, or of M phi purified from such preparations, with PR M-rich wound cell populations obtained 1 day after wounding increased PMN apoptosis by >3-fold. Neither resident- nor Proprionibacterium acnes-elicited peritoneal M phi-induced PMN apoptosis, Apoptosis was not mediated by a soluble factor and required E:T contact. Fixed wound-M phi and membrane isolates from viable M phi were as effective as intact cells in inducing PMN apoptosis. M phi-induced apoptosis was inhibited by peptide Arg-Gly-Asp-Ser, anti-beta(3) (CD61) Ab, CD36 peptide, or anti-TNF-alpha Ab, Soluble TNF-alpha did not induce PMN apoptosis, In additional studies, K562 cells (negative for beta(3), TNF-alpha, and Fas ligand) transfected to express either alpha(v)beta(3) integrin, an uncleavable membrane form of TNF-alpha, or both were used in cocultures with wound PMN, Only the double transfectants were able to induce PMN apoptosis, an effect inhibited by anti-beta(3) (CD61) or anti-TNF-alpha Abs. These results demonstrate that wound M phi, induce PMN apoptosis through a constitutive effector mechanism requiring both intercellular binding through integrin-ligand interactions and membrane-bound TNF-alpha.