Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids.
During the resolution phase of inflammation, apoptotic leukocytes are efferocytosed by macrophages in a nonphlogistic fashion that results in diminished responses to bacterial moieties and production of anti-inflammatory cytokines. Complement receptor 3 and pro-resolving lipid mediators promote the engulfment of apoptotic leukocytes by macrophages. Here, we present evidence for the emergence of pro-resolving, CD11b(low) macrophages in vivo during the resolution of murine peritonitis. These macrophages are distinct from the majority of peritoneal macrophages in terms of their functional protein expression profile, as well as pro-resolving properties, such as apoptotic leukocyte engulfment, indifference to TLR ligands, and emigration to lymphoid organs. Notably, we also found macrophages convert from the CD11b(high) to the CD11b(low) phenotype upon interaction with apoptotic cells ex vivo. In addition, we found that the pro-resolving lipid mediators resolvin E1 and D1, and the glucocorticoid dexamethasone regulated pro-resolving macrophage functions in vivo. This regulation culminated in a novel pro-resolving function, namely reducing the apoptotic leukocyte ingestion requirement for CD11b(low) macrophage generation. These new phenotype and molecular pathway markers define the new satiated macrophage. Thus, we suggest that satisfying efferocytosis generates CD11b(low) macrophages that are essential for complete nonphlogistic containment of inflammatory agents and the termination of acute inflammation.
Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
Sagie
S
Schif-Zuck
Nufar
N
Gross
Simaan
S
Assi
Ran
R
Rostoker
Charles N
CN
Serhan
Amiram
A
Ariel
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001202:Ascitic Fluid / Q000276:immunology / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism*; D002452:Cell Count; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D057899:Cytophagocytosis / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D008198:Lymph Nodes / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors
D039481:CD11b Antigen; D016207:Cytokines; D005938:Glucocorticoids; D011506:Proteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D003907:Dexamethasone; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
Curr Opin Pharmacol. 2005 Aug;5(4):405-11
15955733
FASEB J. 2008 Oct;22(10):3595-606
18559988
Eur J Immunol. 2010 Mar;40(3):699-709
20039295
Nat Immunol. 2005 Dec;6(12):1191-7
16369558
J Exp Med. 1982 Aug 1;156(2):430-42
7097159
J Immunol. 2005 Apr 1;174(7):4345-55
15778399
Trends Immunol. 2007 Apr;28(4):176-83
17337246
Blood. 2009 Feb 26;113(9):2047-55
18952895
J Exp Med. 2002 Dec 16;196(12):1553-61
12486098
Nat Rev Drug Discov. 2004 May;3(5):401-16
15136788
FASEB J. 2004 Nov;18(14):1716-8
15345697
J Exp Med. 2005 Mar 7;201(5):713-22
15753205
Nature. 2002 May 9;417(6885):182-7
12000961
J Clin Invest. 1998 Feb 15;101(4):890-8
9466984
PLoS One. 2008 Apr 02;3(4):e1879
18382663
Immunity. 2010 Apr 23;32(4):518-30
20362473
J Immunol. 2003 Jun 15;170(12):6266-72
12794159
Annu Rev Immunol. 2009;27:451-83
19105661
Trends Immunol. 2004 Dec;25(12):677-86
15530839
J Exp Med. 1998 Dec 21;188(12):2313-20
9858517
J Biol Chem. 2006 Dec 15;281(50):38376-84
17056601
Hum Immunol. 2007 Mar;68(3):156-64
17349870
Histochem Cell Biol. 2004 Oct;122(4):305-21
15322859
Nat Rev Immunol. 2002 Dec;2(12):965-75
12461569
J Immunol. 2002 Feb 15;168(4):1968-77
11823533
J Biol Chem. 2007 Mar 30;282(13):9323-9334
17244615
J Exp Med. 2002 Oct 21;196(8):1025-37
12391014
Immunity. 2004 Nov;21(5):643-53
15539151
J Clin Invest. 2002 Jan;109(1):41-50
11781349
Nat Immunol. 2001 Jul;2(7):612-9
11429545
J Clin Invest. 1992 Oct;90(4):1513-22
1383273
Nat Rev Immunol. 2007 Dec;7(12):964-74
18037898
J Immunol. 2000 Feb 15;164(4):1663-7
10657608
Nat Med. 2002 Nov;8(11):1296-302
12368905
Nature. 1997 Nov 27;390(6658):350-1
9389474
J Immunol. 1996 Sep 15;157(6):2577-85
8805660
FASEB J. 2003 Feb;17(2):253-5
12475898
Blood. 2008 Nov 15;112(10):4117-27
18779392
J Am Soc Nephrol. 2002 Oct;13(10):2497-507
12239238
J Biol Chem. 2005 Dec 30;280(52):43079-86
16216871
Nature. 2007 Jun 14;447(7146):869-74
17568749
J Biol Chem. 2006 Feb 24;281(8):4663-70
16377620