Fc Gamma Receptor IIb on GM-CSF Macrophages Controls Immune Complex Mediated Inhibition of Inflammatory Signals

Background: In rheumatoid arthritis (RA) macrophages play a major role in amplifying synovial inflammation. Important activating signals are those induced by Toll-like receptor (TLR) ligands and by activated T cells. The balance between activating and inhibitory Fc gamma receptors (FccRs) on macrophages might be crucial in modulating these inflammatory responses. The purpose of this study was to determine FccR expression on pro- and anti-inflammatory macrophages (gmMQ and mMQ, respectively) and identify functional consequences on immune complex uptake and macrophage activation. Methods: Human monocytes were isolated and differentiated into gmMQ and mMQ. A full FccR characterization of both macrophage subtypes was performed and uptake of fluorescent immune complexes (ICs) was determined. FccRIIb isoforms were determined by qPCR. Macrophages were stimulated via different TLRs or cytokine activated T cells in the presence or absence of ICs and cytokine production was determined. Blocking studies were performed to look into the pathways involved. Results: mMQ expressed high levels of the activating FccRIIa and FccRIII and low levels of the inhibitory FccRIIb, while the FccR balance on gmMQ was shifted towards the inhibitory FccRIIb. This was accompanied by a clear increase in FccRIIb1 mRNA expression in gmMQ. This resulted in higher IC uptake by mMQ compared to gmMQ. Furthermore, FccR-mediate