A 17-kDa Fragment of Lactoferrin Associates With the Termination of Inflammation and Peptides Within Promote Resolution

Language
en
Document Type
Article
Issue Date
2019-09-03
First published
2018-03-28
Issue Year
2018
Authors
Lutaty, Aviv
Soboh, Soaad
Schif-Zuck, Sagie
Zeituni-Timor, Orly
Rostoker, Ran
Podolska, Malgorzata J.
Schauer, Christine
Herrmann, Martin
Muñoz, Luis E.
Ariel, Amiram
Editor
Publisher
Frontiers Media S.A.
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.

Journal Title
Frontiers in Immunology
Volume
9
Citation
Frontiers in Immunology 9 (2018). <https://www.frontiersin.org/articles/10.3389/fimmu.2018.00644/full>
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