Abstract
BackgroundIn 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 (FcγRs) on macrophages might be crucial in modulating these inflammatory responses. The purpose of this study was to determine FcγR expression on pro- and anti-inflammatory macrophages (gmMφ and mMφ, respectively) and identify functional consequences on immune complex uptake and macrophage activation.MethodsHuman monocytes were isolated and differentiated into gmMφ and mMφ. A full FcγR characterization of both macrophage subtypes was performed and uptake of fluorescent immune complexes (ICs) was determined. FcγRIIb 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.ResultsmMφ expressed high levels of the activating FcγRIIa and FcγRIII and low levels of the inhibitory FcγRIIb, while the FcγR balance on gmMφ was shifted towards the inhibitory FcγRIIb. This was accompanied by a clear increase in FcγRIIb1 mRNA expression in gmMφ. This resulted in higher IC uptake by mMφ compared to gmMφ. Furthermore, FcγR-mediated stimulation of gmMφ inhibited TLR2, 3, 4 and 7/8 mediated cytokine production via FcγRIIb and PI3K signaling. In addition, gmMφ but not mMφ produced TNFα upon co-culture with cytokine activated T cells, which was reduced by IC binding to FcγRIIb. The latter was dependent on PI3K signaling and COX2.ConclusionsFcγR expression patterns on gmMφ and mMφ are significantly different, which translates in clear functional differences further substantiating FcγRIIb as an interesting target for inflammation control in RA and other autoimmune/inflammatory diseases.
Highlights
One of the major pathways underlying the pathogenesis of rheumatoid arthritis (RA) is the aberrant production of inflammatory cytokines by macrophages
The monomeric IgG receptor FccRI was expressed in gmMQ and mMQ, while FccRIII expression was highly increased on mMQ compared to gmMQ
Fc gamma receptors (FccRs) expression was determined on gmMQ and mMQ from some RA patients, which showed a similar FccR distribution compared to healthy controls
Summary
One of the major pathways underlying the pathogenesis of rheumatoid arthritis (RA) is the aberrant production of inflammatory cytokines by macrophages. Many endogenous TLR ligands have been found in an arthritic joint, such as GP96 and SNAPIN, which activate cells via TLR2, small heat shock protein B8 that can activate TLR4, and selfRNA from damaged cells which is likely to stimulate macrophages via TLR3 or TLR7/8 [6,7,8,9,10] Blocking antibodies against these TLRs reduce spontaneous cytokine production by RA synovial tissue cultures, confirming they are present in the arthritic joint and contribute to the abundant cytokine production seen in RA [10,11,12]. 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
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