Effect of Dectin-1 and Fcgr2b on IVIg mediated reprogramming of monocytes

To investigate the role of Dectin-1 and FcgRIIb on monocytes as signaling hubs for IVIg 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 while 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 interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcgRIIb-dependent signaling that required Dectin-1. Comparative gene expression profiling analysis of RNA-seq data for in vivo IVIg primed monocytes sorted from splenocytes of C57BL/6, Dectin-1 -/- and FcgRIIb-/- mice, isolated via Cell sorting; 3 independent mice per group