TY - JOUR
T1 - A 17-kDa fragment of lactoferrin associates with the termination of inflammation and peptides within promote resolution
AU - Lutaty, Aviv
AU - Soboh, Soaad
AU - Schif-Zuck, Sagie
AU - Zeituni-Timor, Orly
AU - Rostoker, Ran
AU - Podolska, Malgorzata J.
AU - Schauer, Christine
AU - Herrmann, Martin
AU - Muñoz, Luis E.
AU - Ariel, Amiram
N1 - Publisher Copyright:
© 2018 Lutaty, Soboh, Schif-Zuck, Zeituni-Timor, Rostoker, Podolska, Schauer, Herrmann, Muñoz and Ariel.
PY - 2018/3/28
Y1 - 2018/3/28
N2 - 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 TNFa 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.
AB - 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 TNFa 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.
KW - Efferocytosis
KW - Lactoferrin
KW - Macrophages
KW - NETosis
KW - Resolution of inflammation
UR - http://www.scopus.com/inward/record.url?scp=85044859613&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2018.00644
DO - 10.3389/fimmu.2018.00644
M3 - Article
C2 - 29643857
AN - SCOPUS:85044859613
SN - 1664-3224
VL - 9
JO - Frontiers in Immunology
JF - Frontiers in Immunology
IS - MAR
M1 - 644
ER -