title: Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling.
abstract: The anti-inflammatory drug high-dose intravenous immunoglobulin, widely used to suppress inflammation, depends on a specific α-2,6-sialylated glycoform of IgG Fc to induce Interleukin 4 (IL-4) and Signal Transducer and Activator of Transcription 6 (STAT6) signaling for its activity. Here we show that anti-inflammatory activities of IL-4 can be attributed to the direct action of this cytokine on myeloid effector cells, depending on their expression of the IL-4 receptor alpha chain (IL-4Rα/CD124). However, in their basal state, these cells express low levels of IL-4Rα and would not be expected to result in significant signaling compared with other cell populations. This apparent paradox can be explained by the observation that during inflammation, triggered by a variety of stimuli (including autoantibodies, adjuvants, and TLR ligands), IL-4Rα is up-regulated specifically on these cells, priming them for STAT6 signaling. The regulation is mediated by a soluble, proteinase K-sensitive factor, released to the circulation by bone marrow-derived, non-B/non-T cells found in several organs, including the lungs, and fat. We propose that this regulation is part of a homeostatic mechanism to limit excessive inflammation and tissue damage. High-dose intravenous immunoglobulin thus exploits an endogenous feedback loop, general to inflammation, that could be further targeted for therapeutic purposes.
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wermeling
authors.forename: Robert M
authors.initials: RM
authors.lastname: Anthony
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000818:Animals; D015153:Blotting, Western; D050824:Carpal Joints / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D006652:Histological Techniques; D006706:Homeostasis / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000378:metabolism / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018709:Statistics, Nonparametric; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D016756:Immunoglobulins, Intravenous; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D050800:STAT6 Transcription Factor; C485701:Fcgr1 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
keywords: macrophages; monocytes; neutrophils
references.citation: Annu Rev Immunol. 1999;17:701-38
references.pmid: 10358772
references.citation: Cytokine Growth Factor Rev. 2006 Oct;17(5):349-66
references.pmid: 16911870
references.citation: J Immunol. 2004 Jun 1;172(11):7186-91
references.pmid: 15153543
references.citation: Immunity. 2002 Feb;16(2):157-68
references.pmid: 11869678
references.citation: Nature. 2003 May 29;423(6939):506-11
references.pmid: 12724780
references.citation: Proc Natl Acad Sci U S A. 1986 Aug;83(15):5654-8
references.pmid: 3090545
references.citation: J Biol Chem. 1997 Feb 28;272(9):5487-94
references.pmid: 9038152
references.citation: Nat Clin Pract Rheumatol. 2006 Aug;2(8):425-33
references.pmid: 16932734
references.citation: Science. 1995 Nov 10;270(5238):985-8
references.pmid: 7481803
references.citation: N Engl J Med. 2008 Feb 28;358(9):929-39
references.pmid: 18305268
references.citation: Science. 2000 Oct 6;290(5489):84-9
references.pmid: 11021804
references.citation: Nat Immunol. 2008 Nov;9(11):1288-96
references.pmid: 18820682
references.citation: N Engl J Med. 1996 Nov 28;335(22):1643-9
references.pmid: 8929361
references.citation: J Immunol. 1997 Dec 1;159(11):5687-96
references.pmid: 9548513
references.citation: Cell. 2008 Jan 25;132(2):259-72
references.pmid: 18243101
references.citation: Immunity. 2001 Jul;15(1):159-72
references.pmid: 11485747
references.citation: J Immunol. 1988 Mar 1;140(5):1548-54
references.pmid: 3279117
references.citation: Nat Rev Immunol. 2008 Jan;8(1):34-47
references.pmid: 18064051
references.citation: J Immunol. 1989 Jun 1;142(11):3857-61
references.pmid: 2785566
references.citation: Eur J Immunol. 2005 Oct;35(10):3064-73
references.pmid: 16180250
references.citation: Arthritis Res. 2000;2(4):293-302
references.pmid: 11056670
references.citation: J Clin Invest. 2006 Jul;116(7):2044-55
references.pmid: 16778988
references.citation: Arthritis Rheum. 1997 Feb;40(2):249-60
references.pmid: 9041936
references.citation: Immunity. 2003 Apr;18(4):573-81
references.pmid: 12705859
references.citation: J Exp Med. 1982 Mar 1;155(3):914-23
references.pmid: 6977612
references.citation: Nature. 2011 Jun 19;475(7354):110-3
references.pmid: 21685887
references.citation: Lancet. 1993 Oct 16;342(8877):945-9
references.pmid: 8105212
references.citation: Curr Opin Immunol. 2011 Oct;23(5):598-604
references.pmid: 21889323
references.citation: Annu Rev Immunol. 2008;26:513-33
references.pmid: 18370923
references.citation: Eur J Immunol. 2012 Apr;42(4):826-30
references.pmid: 22278120
references.citation: Lancet. 2005 Jan 1-7;365(9453):63-78
references.pmid: 15639681
references.citation: Science. 2006 Aug 4;313(5787):670-3
references.pmid: 16888140
references.citation: Arthritis Rheum. 2010 Mar;62(3):753-64
references.pmid: 20191628
references.citation: Proc Natl Acad Sci U S A. 1988 Nov;85(21):8221-5
references.pmid: 3263648
references.citation: Arthritis Rheum. 2007 Mar;56(3):861-70
references.pmid: 17330244
references.citation: Nature. 1992 Mar 26;356(6367):314-7
references.pmid: 1372394