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Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of Fc?RIIB 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 Fc?RIIB and the C-type lectin–like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of Fc?RIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain–containing inositol phosphatase (SHIP) downstream of Fc?RIIB 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 Fc?RIIB and dectin-1. Thus, galactosylated IgG1 and Fc?RIIB exert anti-inflammatory properties beyond their impact on activating Fc?Rs.

SUBMITTER: Karsten CM

PROVIDER: S-EPMC3492054 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Karsten Christian M CM Pandey Manoj K MK Figge Julia J Kilchenstein Regina R Taylor Philip R PR Rosas Marcela M McDonald Jacqueline U JU Orr Selinda J SJ Berger Markus M Petzold Dominique D Blanchard Veroniqué V Winkler André A Hess Constanze C Reid Delyth M DM Majoul Irina V IV Strait Richard T RT Harris Nathaniel L NL Köhl Gabriele G Wex Eva E Ludwig Ralf R Zillikens Detlef D Nimmerjahn Falk F Finkelman Fred D FD Brown Gordon D GD Ehlers Marc M Köhl Jörg J

Nature medicine 20120901 9

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 r ...[more]

PMID: 22922409

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Project description:Fc? receptors (Fc?Rs) are classified as activating (Fc?RI, III, and IV) and inhibitory (Fc?RII) receptors. We have reported that deletion of activating Fc?Rs in apolipoprotein E (apoE) single knockout mice attenuated atherosclerosis. In this report, we investigated the hypothesis that deficiency of inhibitory Fc?RIIb exacerbates atherosclerosis.ApoE-Fc?RIIb double knockout mice, congenic to the C57BL/6 (apoE-Fc?RIIbB6 (-/-)), were generated and atherosclerotic lesions were assessed. In contrary to our hypothesis, when compared with apoE single knockout mice, arterial lesions were significantly decreased in apoE-Fc?RIIbB6 (-/-) male and female mice fed chow or high-fat diets. Chimeric mice generated by transplanting apoE-Fc?RIIbB6 (-/-) marrow into apoE single knockout mice also developed reduced lesions. CD4(+) T cells from apoE-Fc?RIIbB6 (-/-) mice produced higher levels of interleukin-10 and transforming growth factor-? than their apoE single knockout counterparts. As our findings conflict with a previous report using apoE-Fc?RIIb129/B6 (-/-) mice on a mixed genetic background, we investigated whether strain differences contributed to the anti-inflammatory response. Macrophages from Fc?RIIb129/B6 (-/-) mice on a mixed genetic background produced more interleukin-1? and MCP-1 (monocyte chemoattractant protein-1) in response to immune complexes, whereas congenic Fc?RIIbB6 (-/-) mice generated more interleukin-10 and significantly less interleukin-1?. Interestingly, the expression of lupus-associated slam genes, located in proximity to fcgr2b in mouse chromosome 1, is upregulated only in mixed Fc?RIIb129/B6 (-/-) mice.Our findings demonstrate a detrimental role for Fc?RIIb signaling in atherosclerosis and the contribution of anti-inflammatory cytokine responses in the attenuated lesions observed in apoE-Fc?RIIbB6 (-/-) mice. As 129/sv genome-derived lupus-associated genes have been implicated in lupus phenotype in Fc?RIIb129/B6 (-/-) mice, our findings suggest possible epistatic mechanism contributing to the decreased lesions.

Dataset Information

Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of Fc?RIIB and dectin-1.

Publications

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

Similar Datasets

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