Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB.
Cells of the monocyte-macrophage lineage play a central role in the orchestration and resolution of inflammation. Plasticity is a hallmark of mononuclear phagocytes, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic or M1 and alternative or M2. NF-kappaB is a key regulator of inflammation and resolution, and its activation is subject to multiple levels of regulation, including inhibitory, which finely tune macrophage functions. Here we identify the p50 subunit of NF-kappaB as a key regulator of M2-driven inflammatory reactions in vitro and in vivo. p50 NF-kappaB inhibits NF-kappaB-driven, M1-polarizing, IFN-beta production. Accordingly, p50-deficient mice show exacerbated M1-driven inflammation and defective capacity to mount allergy and helminth-driven M2-polarized inflammatory reactions. Thus, NF-kappaB p50 is a key component in the orchestration of M2-driven inflammatory reactions.
Porta
Chiara
C
Fondazione Humanitas per la Ricerca, 20089 Rozzano, Italy.
Rimoldi
Monica
M
Raes
Geert
G
Brys
Lea
L
Ghezzi
Pietro
P
Di Liberto
Diana
D
Dieli
Francesco
F
Ghisletti
Serena
S
Natoli
Gioacchino
G
De Baetselier
Patrick
P
Mantovani
Alberto
A
Sica
Antonio
A
D000818:Animals; D016764:Cell Polarity; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D016899:Interferon-beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism
D004731:Endotoxins; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016899:Interferon-beta
Nature. 2007 Jun 21;447(7147):972-8
17538624
Cancer Res. 2006 Dec 1;66(23):11432-40
17145890
Trends Immunol. 2004 Jun;25(6):280-8
15145317
Nat Rev Immunol. 2007 May;7(5):353-64
17457343
Trends Immunol. 2004 Dec;25(12):677-86
15530839
J Immunol. 2004 Dec 15;173(12):7416-25
15585867
Parasitol Res. 2001 Oct;87(10):826-32
11688888
J Endotoxin Res. 2005;11(5):311-20
16263005
Nat Rev Immunol. 2005 Jun;5(6):446-58
15928677
J Exp Med. 1998 Nov 2;188(9):1739-50
9802985
Cell. 1995 Feb 24;80(4):529-32
7867060
Vet Parasitol. 2007 Aug 19;148(1):3-13
17560035
J Clin Invest. 2007 May;117(5):1155-66
17476345
J Inflamm. 1995;45(1):13-26
7583350
J Clin Invest. 1998 Nov 1;102(9):1645-52
9802878
J Immunol. 2005 Jun 1;174(11):6561; author reply 6561-2
15905489
N Engl J Med. 2003 Jan 9;348(2):138-50
12519925
J Biol Chem. 1997 Jan 10;272(2):1226-30
8995425
J Immunol. 2005 Feb 15;174(4):1801-10
15699106
Immunity. 2005 Oct;23(4):344-6
16226499
Scand J Infect Dis. 2003;35(9):555-62
14620134
Immunity. 2004 Aug;21(2):227-39
15308103
J Exp Med. 2003 Nov 3;198(9):1391-402
14597738
J Immunol. 2003 Jan 1;170(1):508-19
12496438
Infect Immun. 2002 Jul;70(7):3656-64
12065507
J Immunol. 2004 Apr 1;172(7):4410-7
15034056
J Exp Med. 1990 Jun 1;171(6):1853-69
2112583
Nature. 2007 May 3;447(7140):92-6
17450126
Science. 2004 Jun 11;304(5677):1678-82
15192232
J Immunol. 2006 Nov 15;177(10):7303-11
17082649
Immunity. 1999 Feb;10(2):137-42
10072066
J Immunol. 2003 Jan 1;170(1):270-8
12496409
Trends Immunol. 2002 Nov;23(11):549-55
12401408
J Endotoxin Res. 2001;7(3):219-22
11581573
Crit Care. 2006;10(5):233
17044947
Dev Immunol. 2002 Sep;9(3):151-9
12892049
Immunity. 2000 Oct;13(4):539-48
11070172
Blood. 2006 Mar 1;107(5):2112-22
16269622
J Immunol. 2005 May 15;174(10):6095-104
15879104
J Virol. 1994 Aug;68(8):4707-15
8035474
J Immunol. 2000 Jan 15;164(2):762-7
10623821
J Leukoc Biol. 2007 Aug;82(2):347-53
17475783
Nat Rev Immunol. 2002 Oct;2(10):725-34
12360211
Nat Rev Immunol. 2005 Dec;5(12):953-64
16322748
Blood. 2009 Apr 2;113(14):3139-46
19171876
Toxicol Sci. 2005 Dec;88(2):420-33
16141432