Fc Gamma Receptor IIb on GM-CSF Macrophages Controls Immune Complex Mediated Inhibition of Inflammatory Signals: e110966

• Published in: PloS one 2014-10, Vol.9 (10)
• Main Authors: Santegoets, Kim CM, Wenink, Mark H, Berg, B vanden, Radstake, R DJ
• Format: Article
• Language: English
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0110966

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 (Fc gamma Rs) on macrophages might be crucial in modulating these inflammatory responses. The purpose of this study was to determine Fc gamma R expression on pro- and anti-inflammatory macrophages (gmM phi and mM phi , respectively) and identify functional consequences on immune complex uptake and macrophage activation. Methods Human monocytes were isolated and differentiated into gmM phi and mM phi . A full Fc gamma R characterization of both macrophage subtypes was performed and uptake of fluorescent immune complexes (ICs) was determined. Fc gamma RIIb 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 mM phi expressed high levels of the activating Fc gamma RIIa and Fc gamma RIII and low levels of the inhibitory Fc gamma RIIb, while the Fc gamma R balance on gmM phi was shifted towards the inhibitory Fc gamma RIIb. This was accompanied by a clear increase in Fc gamma RIIb1 mRNA expression in gmM phi . This resulted in higher IC uptake by mM phi compared to gmM phi . Furthermore, Fc gamma R-mediated stimulation of gmM phi inhibited TLR2, 3, 4 and 7/8 mediated cytokine production via Fc gamma RIIb and PI3K signaling. In addition, gmM phi but not mM phi produced TNF alpha upon co-culture with cytokine activated T cells, which was reduced by IC binding to Fc gamma RIIb. The latter was dependent on PI3K signaling and COX2. Conclusions Fc gamma R expression patterns on gmM phi and mM phi are significantly different, which translates in clear functional differences further substantiating Fc gamma RIIb as an interesting target for inflammation control in RA and other autoimmune/inflammatory diseases.