Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1

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-inflam-matory 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 FcgRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcgRIIb membrane conformations that allowed productive IgG binding and enhanced in-teractions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcgRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co -inhib-itory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.

Automated summary

Immunoglobulin G (IgG) antibodies are major drivers of inflammation, but in pooled serum IgG (IVIg), they have immunomodulatory and anti-inflammatory activity. The mechanism behind this activity is unclear. The study found that IVIg sialylation inhibited joint inflammation in rheumatoid arthritis models, and the inhibition of osteoclastogenesis was independent of sialic acid. Instead, IVIg-dependent inhibition of osteoclastogenesis required the presence of receptors Dectin-1 or FcgRIIb. This research reveals a novel role of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of osteoclastogenesis.