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Anti-Inflammatory Activity of Igg1 Mediated by Fc Galactosylation And

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Anti-Inflammatory Activity of Igg1 Mediated by Fc Galactosylation And LETTERS Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1 Christian M Karsten1,14, Manoj K Pandey2,14, Julia Figge1, Regina Kilchenstein1, Philip R Taylor3, Marcela Rosas3, Jacqueline U McDonald3, Selinda J Orr3, Markus Berger4, Dominique Petzold4, Veroniqué Blanchard4, André Winkler5, Constanze Hess5, Delyth M Reid6, Irina V Majoul7, Richard T Strait8, Nathaniel L Harris2, Gabriele Köhl1, Eva Wex9, Ralf Ludwig10, Detlef Zillikens10, Falk Nimmerjahn11, Fred D Finkelman2,12,13, Gordon D Brown6, Marc Ehlers1,5 & Jörg Köhl1,2 Complement is an ancient danger-sensing system that FcγRs2. FcR γ-chain–deficient (Fcer1g−/−) mice express no functional contributes to host defense, immune surveillance and activating FcγRs but do express the inhibitory FcγRIIB. These mice homeostasis1. C5a and its G protein–coupled receptor mediate are protected from IC-mediated inflammation despite the presence of many of the proinflammatory properties of complement2. C5a. We hypothesized that one mechanism underlying such protec- Despite the key role of C5a in allergic asthma3, autoimmune tion could be an anti-inflammatory property of IgG ICs suppressing arthritis4, sepsis5 and cancer6, knowledge about its regulation C5a-mediated effector functions. is limited. Here we demonstrate that IgG1 immune complexes To test our hypothesis, we injected C5a into the peritoneal cavity of (ICs), the inhibitory IgG receptor FcgRIIB and the C-type BALB/c wild-type (WT) or Fcer1g−/− mice. As expected, neutrophils lectin–like receptor dectin-1 suppress C5a receptor (C5aR) were recruited into the peritoneum in both mouse strains (Fig. 1a). functions. IgG1 ICs promote the association of FcgRIIB with IgG1 is the most abundant isotype of serum antibody in mice. The dectin-1, resulting in phosphorylation of Src homology 2 preferential binding of IgG1 to inhibitory FcγRIIB is considered a domain–containing inositol phosphatase (SHIP) downstream of protective mechanism to prevent incidental activation of circulating FcgRIIB and spleen tyrosine kinase downstream of dectin-1. myeloid cells by binding of ICs to activating FcγRs12. Intravenous injec- This pathway blocks C5aR-mediated ERK1/2 phosphorylation, tion of the trinitrophenyl (TNP)-specific IC comprising IgG1 clone C5a effector functions in vitro and C5a-dependent 107.3 and TNP-OVA (107.3-IC)13 30 min before C5a administration inflammatory responses in vivo, including peritonitis and reduced C5a-mediated neutrophil migration into the peritoneum in −/− −/− © All rights reserved. 2012 Inc. Nature America, skin blisters in experimental epidermolysis bullosa acquisita. WT and Fcer1g mice but not in FcγRIIB-deficient (Fcgr2b ) mice Notably, high galactosylation of IgG N-glycans is crucial for this (Fig. 1a and Supplementary Fig. 1). Monomeric 107.3 antibody did inhibitory property of IgG1 ICs, as it promotes the association not have an anti-inflammatory effect (data not shown). We have previ- between FcgRIIB and dectin-1. Thus, galactosylated IgG1 ously shown that the peritoneal inflammation induced by ovalbumin and FcgRIIB exert anti-inflammatory properties beyond their (OVA)-specific ICs is mediated by C5a11. Pretreatment with 107.3-IC impact on activating FcgRs. blocked OVA-IC–induced peritonitis in WT but not Fcgr2b−/− mice, demonstrating a crucial role for FcγRIIB in 107.3-IC–mediated inhibi- Activating FcγRs and C5aR promote inflammatory responses in tion of C5a-dependent inflammation (Fig. 1b). experimental autoimmune nephritis7,8, arthritis9, IC alveolitis10 The mechanisms underlying C5aR-mediated extravasation and tissue 11 and peritonitis . C5a decreases the cellular activation threshold by recruitment of neutrophils involve the β2 integrin heterodimer upregulating the ratio of activating to inhibitory FcγRs (known as the CD11b and CD18 (CR3)14. C5a upregulated CD11b expression on A/I ratio)10,11. Activating FcγRs eventually drive proinflammatory neutrophils from WT (data not shown) and Fcer1g−/− mice in a effector functions12. C5a also recruits and activates inflammatory cells dose-dependent manner (Supplementary Fig. 2), and this upregu- such as neutrophils, macrophages and mast cells independently of lation was significantly reduced upon 107.3-IC pretreatment and was 1Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany. 2Division of Cellular and Molecular Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 3Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK. 4Glycodesign and Glycoanalytics, Central Institute of Laboratory Medicine and Pathobiochemistry, Charité Medical University, Berlin, Germany. 5Laboratory of Tolerance and Autoimmunity, German Rheumatism Research Center, Berlin, Germany. 6Section of Infection and Immunity, University of Aberdeen, Aberdeen, UK. 7Institute of Biology, Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany. 8Division of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 9Department of Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH, Biberach, Germany. 10Department of Dermatology, University of Lübeck, Lübeck, Germany. 11Department of Biology, Chair of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany. 12Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 13Department of Medicine, Cincinnati Veterans Affairs Medical Center Cincinnati, Ohio, USA. 14These authors contributed equally to this work. Correspondence should be addressed to J.K. ([email protected]). Received 11 October 2011; accepted 12 June 2012; published online 26 August 2012; doi:10.1038/nm.2862 NATURE MEDICINE ADVANCE ONLINE PUBLICATION 1 LETTERS a WT Fcer1g–/– Fcgr2b–/– b c 200 200 200 300 s *** s Fcer1g–/– Fcgr2b–/– *** 150 150 150 *** 1,100 1,100 2 2 2 2 200 1,050 1,050 b *** b 100 100 100 1,000 1,000 950 950 per mm per mm per mm per mm 100 50 50 50 900 900 MFI CD11 850 MFI CD11 850 Number of neutrophil Number of neutrophils Number of neutrophil 0 Number of neutrophils 0 0 0 800 800 + –/– –/– + 1 1 –/– 0.1 0.1 C5a C5a C5a 0.01 0.01 Ag CtrlAb Ctrl 107.3-IC 107.3-IC 107.3-IC Untreated Untreated Untreated 107.3-IC Fcer1gFcgr2bFcgr2b107.3-IC Untreated Untreated 107.3-IC (µg ml–1) 107.3-IC (µg ml–1) Peritonitis WT C5a + 107.3-IC C5a + 107.3-IC C5a + 107.3-IC Peritonitis WT + 107.3-IC PeritonitisPeritonitis Peritonitis e WT Fcer1g–/– Fcgr2b–/– f WT Fcer1g–/– Fcgr2b–/– Medium –1 *** 2,000 * 2,000 3,000 107.3-IC 1 µg ml 150 150 *** 150 d –1 *** * 107.3-IC 0.01 µg ml 1,500 1,500 2 *** 2 2 *** 2,000 Fcer1g–/– 100 100 100 35 ** 1,000 1,000 30 peak height peak height 50 50 50 peak height 1,000 per mm per mm 25 * per mm 500 500 2+ 2+ 20 2+ Ca Ca 15 0 0 0 0 Ca 0 0 10 Number of neutrophils Number of neutrophils Number of neutrophils Neutrophil 5 1 1 1 adhesion (%) 0.1 0.1 0.1 0 0.01 0.01 0.01 C5a C5a C5a 0.1 1 10 107.3-IC 107.3-IC 107.3-IC Untreated Untreated Untreated C5a (nM) 107.3-IC (µg ml–1) 107.3-IC (µg ml–1) 107.3-IC (µg ml–1) C5a + 107.3-IC C5a + 107.3-IC C5a + 107.3-IC 20 Fcgr2b–/– g h 1,024 100 100 100 80 15 100 Ctrl 107.3-IC 107.3-IC C5aRA Gr-1APC –1 –1 768 75 75 0.1 µg ml 75 1 µg ml 60 5 × 10–5 M 10 75 512 50 50 50 50 40 5 Neutrophil SSC-H 256 25 25 25 25 20 adhesion (%) 0 0 Counts 0 Counts 0 0 0 0 0.1 1 10 0 256 512 768 1,024 100 101 102 103 104 100 101 102 103 104 100 101 102 103 104 100 101 102 103 104 C5a (nM) FSC-H Gr-1 P-ERK1/2 Figure 1 IgG1-ICs inhibit C5a-mediated inflammatory responses in vivo and in vitro by an FcγRIIB-dependent mechanism. (a,b) Peritoneal migration of neutrophils in response to C5a (a) or OVA-ICs comprising OVA and OVA-specific rabbit IgG (b) with or without 107.3-ICs in WT, Fcer1g−/− or Fcgr2b−/− mice. (c,d) Impact of 107.3-ICs on CD11b expression (c) and iC3b-dependent adhesion (d) in bone marrow–derived neutrophils from Fcer1g−/− and Fcgr2b−/− 2+ mice. MFI, mean fluorescence intensity. (e,f) C5a-mediated migration of bone marrow–derived neutrophils (e) and increase in [Ca ]i in bone marrow– derived cells (f) from WT, Fcer1g−/− or Fcgr2b−/− mice with or without 107.3-ICs. (g) Gating of bone marrow–derived neutrophils according to their cell size (FSC) and granularity (SSC) pattern (left dot plot) and the expression of the Gr-1 marker (histogram on the right). (h) Dose-dependent impact of 107.3-ICs on C5a-mediated ERK1/2 phosphorylation in Gr-1+ WT bone marrow–derived neutrophils (three graphs on the left) and the effect of the C5a receptor antagonist A8∆71−73(C5aRA) on C5a-mediated ERK1/2 phosphorylation in bone marrow–derived neutrophils (graph on the right). Empty histogram, ERK phosphorylation in the absence of C5a (background); gray histogram, treatment with C5a (5 × 10−8 M; 1 min); magenta histogram, C5a (5 × 10−8 M; 1 min) + 107.3-ICs or C5aRA at the indicated concentrations. Results in c and g are representative of at least three independent experiments. Values in a,b,d–f are means ± s.e.m. (n = 5–10 per group). *P < 0.05, **P < 0.01, ***P < 0.001. © All rights reserved. 2012 Inc. Nature America, absent with cells from Fcgr2b−/− mice (Fig. 1c). 107.3-IC administra- but not from Fcgr2b−/− mice (Fig. 1f). Next, we tested the impact of tion also reduced C5a-dependent neutrophil adhesion among cells 107.3-ICs on C5a-mediated ERK1/2 phosphorylation in Gr1+ bone from Fcer1−/− but not Fcgr2b−/− mice (Fig.
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