Article ; Online: Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1.
2023 Volume 56, Issue 5, Page(s) 1046–1063.e7
Abstract: Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is ... ...
| Abstract | Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation. |
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| MeSH term(s) | Animals ; Humans ; Mice ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/immunology ; Cell Membrane/metabolism ; Immunoglobulins, Intravenous/administration & dosage ; Lectins, C-Type/metabolism ; Mice, Inbred C57BL ; Osteoclasts/metabolism ; Protein Processing, Post-Translational ; Receptors, IgG/metabolism | ||||||||||
| Chemical Substances | CLEC7A protein, human ; Clec7a protein, mouse ; Fc gamma receptor IIB ; Immunoglobulins, Intravenous ; Lectins, C-Type ; Receptors, IgG | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2023-03-21 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 1217235-2 | ||||||||||
| ISSN | 1097-4180 ; 1074-7613 | ||||||||||
| ISSN (online) | 1097-4180 | ||||||||||
| ISSN | 1074-7613 | ||||||||||
| DOI | 10.1016/j.immuni.2023.02.019 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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