title: Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1.
abstract: Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis. C5a and its G protein–coupled receptor mediate many of the proinflammatory properties of complement. Despite the key role of C5a in allergic asthma, autoimmune arthritis, sepsis and cancer, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor FcγRIIB and the C-type lectin–like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of FcγRIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain–containing inositol phosphatase (SHIP) downstream of FcγRIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between FcγRIIB and dectin-1. Thus, galactosylated IgG1 and FcγRIIB exert anti-inflammatory properties beyond their impact on activating FcγRs.
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Karsten
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Pandey
authors.forename: Julia
authors.initials: J
authors.lastname: Figge
authors.forename: Regina
authors.initials: R
authors.lastname: Kilchenstein
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Marcela
authors.initials: M
authors.lastname: Rosas
authors.forename: Jacqueline U
authors.initials: JU
authors.lastname: McDonald
authors.forename: Selinda J
authors.initials: SJ
authors.lastname: Orr
authors.forename: Markus
authors.initials: M
authors.lastname: Berger
authors.forename: Dominique
authors.initials: D
authors.lastname: Petzold
authors.forename: Veroniqué
authors.initials: V
authors.lastname: Blanchard
authors.forename: André
authors.initials: A
authors.lastname: Winkler
authors.forename: Constanze
authors.initials: C
authors.lastname: Hess
authors.forename: Delyth M
authors.initials: DM
authors.lastname: Reid
authors.forename: Irina V
authors.initials: IV
authors.lastname: Majoul
authors.forename: Richard T
authors.initials: RT
authors.lastname: Strait
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Harris
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhl
authors.forename: Eva
authors.initials: E
authors.lastname: Wex
authors.forename: Ralf
authors.initials: R
authors.lastname: Ludwig
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.forename: Marc
authors.initials: M
authors.lastname: Ehlers
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal; D001327:Autoimmune Diseases / Q000276:immunology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D015936:Complement C5a / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D000072377:Syk Kinase; D000099181:Dectin-1
chemical_list: D000911:Antibodies, Monoclonal; D002118:Calcium; D015936:Complement C5a; D007074:Immunoglobulin G; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D010744:Phosphoric Monoester Hydrolases; D011505:Protein-Tyrosine Kinases; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D017452:Receptors, IgG; D000072377:Syk Kinase; D000099181:Dectin-1; C488033:C5AR1 protein, human; C000606896:SYK protein, human; C000606897:Syk protein, mouse