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Front. Immunol. | doi: 10.3389/fimmu.2018.00644

A 17 kDa fragment of lactoferrin associates with the termination of inflammation and peptides within promote resolution

  • 1Department of Biology, University of Haifa, Israel
  • 2Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany

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 TNFalpha and IL-6 and increased IL-10 secretion by LPS-stimulated macrophages ex vivo. In addition, FKE promoted neutrophil-mediated resolution at high concentrations (100 microM) by enhancing the formation of cytokine-scavenging aggregated NETs (tophi) at low cellular density. Thus, PMN lactoferrin is processed, acquired, and "recycled" by neutrophils and macrophages during inflammation resolution to generate fragments and peptides with paramount pro-resolving activities.

Keywords: resolution of inflammation, Macrophages, Efferocytosis, Lactoferrin, NEtosis

Received: 23 Aug 2017; Accepted: 14 Mar 2018.

Edited by:

Céline Cougoule, Centre national de la recherche scientifique (CNRS), France

Reviewed by:

Lucy V. Norling, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
Werner Solbach, University of Lübeck, Germany  

Copyright: © 2018 Lutaty, Soboh, Schif-Zuck, Zeituni-Timor, Rostoker, Podolska, Munoz, Schauer, Herrmann and Ariel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Amiram Ariel, University of Haifa, Department of Biology, Mt. Carmel, Haifa, 31905, Israel,