Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1

Christian M Karsten, Manoj K Pandey, Julia Figge, Regina Kilchenstein, Philip R Taylor, Marcela Rosas, Jacqueline U McDonald, Selinda J Orr, Markus Berger, Dominique Petzold, Veroniqué Blanchard, André Winkler, Constanze Hess, Delyth M Reid, Irina V Majoul, Richard T Strait, Nathaniel L Harris, Gabriele Köhl, Eva Wex, Ralf LudwigDetlef Zillikens, Falk Nimmerjahn, Fred D Finkelman, Gordon D Brown, Marc Ehlers, Jörg Köhl

Research output: Contribution to journalLetter

240 Citations (Scopus)

Abstract

Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis1. C5a and its G protein–coupled receptor mediate many of the proinflammatory properties of complement2. Despite the key role of C5a in allergic asthma3, autoimmune arthritis4, sepsis5 and cancer6, 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.
Original languageEnglish
Pages (from-to)1401-1406
Number of pages6
JournalNature Medicine
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 2012

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