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

• Published in: Immunity (Cambridge, Mass.) Vol. 56; no. 5; pp. 1046 - 1063.e7
• Main Authors: Seeling, Michaela, Pöhnl, Matthias, Kara, Sibel, Horstmann, Nathalie, Riemer, Carolina, Wöhner, Miriam, Liang, Chunguang, Brückner, Christin, Eiring, Patrick, Werner, Anja, Biburger, Markus, Altmann, Leon, Schneider, Martin, Amon, Lukas, Lehmann, Christian H.K., Lee, Sooyeon, Kunz, Meik, Dudziak, Diana, Schett, Georg, Bäuerle, Tobias, Lux, Anja, Tuckermann, Jan, Vögtle, Timo, Nieswandt, Bernhardt, Sauer, Markus, Böckmann, Rainer A., Nimmerjahn, Falk
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.05.2023
• Subjects: Animals; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; bone; Cell Membrane - metabolism; Dectin-1; Fc-receptor; glycosylation; Humans; IgG; Immunoglobulins, Intravenous - administration & dosage; inflammation; Lectins, C-Type - metabolism; Mice; Mice, Inbred C57BL; osteoclast; Osteoclasts - metabolism; Protein Processing, Post-Translational; Receptors, IgG - metabolism; rheumatoid arthritis; Dectin-1; inflammation; IgG; glycosylation; bone; Fc-receptor; osteoclast; rheumatoid arthritis
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.02.019

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. [Display omitted] •Separate pathways trigger IgG-dependent resolution of joint versus bone inflammation•Dectin-1 is required for IVIg-mediated suppression of osteoclastogenesis•IVIg reprograms monocytes via the Dectin-1/FcγRIIb axis•Dectin-1 enhances monomeric IgG binding to the low-affinity inhibitory FcγRIIb Intravenous immunoglobulins (IVIg) efficiently trigger resolution of inflammation; yet, the underlying pathways of IVIg-dependent immunomodulation remain poorly understood. Seeling et al. demonstrate that IVIg initiates resolution of inflammatory bone loss via a Dectin-1-dependent modulation of IVIg binding to the inhibitory FcγRIIb, leading to a reprogramming of inflammatory monocytes.