Abstract
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) and fragments thereof in vivo and ex vivo. 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, accumulation, and release were mediated initially by neutrophils and later by efferocytic macrophages. The 17-kDa fragment contained two bioactive tripeptides, FKD and FKE that promoted resolution phase macrophage conversion to a pro-resolving phenotype. This resulted in a reduction in peritoneal macrophage numbers and an increase in the CD11blow subset of these cells. Moreover, FKE, but not FKD, peptides enhanced efferocytosis of apoptotic PMN, reduced TNFα and interleukin (IL)-6, and increased IL-10 secretion by lipopolysaccharide-stimulated macrophages ex vivo. In addition, FKE promoted neutrophil-mediated resolution at high concentrations (100 µM) by enhancing the formation of cytokine-scavenging aggregated NETs (tophi) at a low cellular density. Thus, PMN Lf is processed, acquired, and “recycled” by neutrophils and macrophages during inflammation resolution to generate fragments and peptides with paramount pro-resolving activities.
Highlights
The clearance of apoptotic cells is essential for proper development, homeostasis, and the termination of immune responses [1, 2]
We hypothesized that Lf is acquired by macrophages once they engulf senescent polymorphonuclear cells (PMN)
These results indicate that Lf was processed, at least partially, in neutrophils during the apoptotic process, and Lf and its fragments were acquired by resolution phase macrophages following the phagocytosis of apoptotic cells
Summary
The clearance of apoptotic cells is essential for proper development, homeostasis, and the termination of immune responses [1, 2]. The engulfment of apoptotic polymorphonuclear cells (PMN) by macrophages during the resolution of inflammation, in particular, is considered to be a hallmark and a major fate-determining event for these cells [3,4,5,6]. Neutrophil-derived defensins were preserved and transferred from engulfed apoptotic PMN to the phagolysosomes in the engulfing macrophage [8]. They limit the intracellular growth of Mycobacterium tuberculosis. It has been shown that CD11blow macrophages emerge during the resolution of inflammation [9] These satiated phagocytes engulf high numbers of apoptotic PMN and consecutively migrate to spleen and inguinal lymph nodes (LN) [9]
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