Rheumatoid Arthritis-associated IgG N-glycan agalactosylation diminishes neutrophilic inflammation by reducing FcgammaR binding and downstream signaling

Abstract

The IgG Fc chain carries a single N-linked glycan which may undergo changes. Increased agalactosylated N-glycans are associated with rheumatoid arthritis (RA) and regarded as pro-inflammatory. Dysregulated neutrophils can make important contributions to host tissue damage. In RA, immune complexes (ICs) that have precipitated onto synovial joint surfaces activate neutrophils via Fc receptors, promoting localised inflammation. We engineered recombinant human monoclonal IgG with agalactosylated or galactosylated N-glycans, generated immobilised ICs and stimulated healthy donor and RA patient blood-derived neutrophils, comparing reactive oxygen species (ROS) production as read-out of neutrophilic inflammation. Both healthy donor and RA patient neutrophils generated less ROS when stimulated with ICs made from agalactosylated IgG. Mechanistically this was due to poorer binding of agalactosylated ICs to neutrophil Fc{gamma}Rs, causing lower activation of Akt and p38 MAPK. Both are required for immobilised IC-mediated stimulation of the neutrophil NADPH oxidase. Taken together, this suggests that disease-associated, agalactosylated IgG does not in fact promote inflammation and host tissue injury, at least not by acting on neutrophils. We propose that rather than promoting inflammation, agalactosylated IgG N-glycans that accompany inflammatory disease may arise as part of a compensatory mechanism that is aimed at reducing excessive inflammation and host tissue injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/735866v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@18a7178org.highwire.dtl.DTLVardef@1f8d75org.highwire.dtl.DTLVardef@1801a22org.highwire.dtl.DTLVardef@133e657_HPS_FORMAT_FIGEXP M_FIG C_FIG