Updated project metadata. During the resolution of inflammation macrophages engulf apoptotic polymorphonuclear cells (PMN) and can accumulate large numbers of their corpses. Here we report that resolution-phase-macrophages acquire the neutrophil-derived glycoprotein lactoferrin (Lf) in vivo and ex vivo and process it to short fragments. During the onset and resolving phases of inflammation in murine peritonitis and bovine mastitis Lf fragments of 15 and 17 kDa occurred in various body fluids, and the murine fragmentation and release were mediated by macrophages. The 17 kDa fragment contained two bioactive tripeptides, FKD and FKE that promoted human macrophage reprogramming to a pro-resolving phenotype. At low concentrations (1-10 M) this was reflected by inhibition of LPS-induced TNFand IL-6 secretion and increased IL-10 levels. Both peptides inhibited ERK and cJun activation following macrophage exposure to LPS. In addition, FKD, and to a lesser extent FKE, promoted neutrophil-mediated resolution at high concentrations (30-100 M) by enhancing the formation of cytokine-scavenging aggregated NETs at low cellular density. Thus, PMN lactoferrin is acquired, processed and