Background There is extensive published literature about the interaction of monosodium urate (MSU) crystals with immune cells, however, less information exists about the impact of soluble uric acid (SUA) on these cells. As deposits of MSU crystals can be present in asymptomatic joints, and changes in uric acid levels can initiate an arthritis flare in gout patients, we investigated the effect of SUA on the response of macrophages to MSU crystals.
Objectives To analyze the effect of SUA on macrophage polarization and function of M-CSF polarized M2-like macrophages.
Methods Blood was collected from healthy donors after informed consent. Peripheral blood mononuclear cells (PBMC) were separated from whole blood by centrifugation with a density gradient. Monocytes were then isolated by negative selection with magnetic beads and cultured for 1 week with M-CSF (20 ng/ml) in the presence or absence of biologically relevant concentrations of SUA (0.3 mM and 0.6 mM representing normouricemia and hyperuricemia respectively). Macrophages were then stimulated with MSU (200 μg/mL), LPS (100 ng/mL) or both for 18 hours. Alternatively, M-CSF polarized M2-like macrophages were generated and subsequently exposed to SUA for 24 hours prior to stimulation with MSU and LPS. MSU phagocytosis and cell viability were analyzed by flow cytometry. IL-1β and IL-10 concentrations in culture supernatants were quantified by ELISA. Flow cytometry and statistical analyses were performed with FACSDiva and GraphPad Prism 5 softwares respectively.
Results M2 macrophages polarized in the presence of SUA produced less IL-1β upon challenging with MSU and LPS, that was most significant in conditions equivalent to hyperuricemia (0.6mM), whereas there was a modest inhibitory effect on IL-10 production only for macrophages exposed to high uric acid concentrations. On the other hand, exposure of already polarized macrophages to both low and high concentrations of SUA notably suppressed both IL-1β and IL-10 production. No differences in phagocytosis or cell viability were observed with exposure to SUA either during or after macrophage polarization.
Conclusions Unexpectedly, our results show that SUA exerts a suppressive effect on MSU-induced IL-1β and IL-10 production by M-CSF polarized macrophages. To our knowledge this is the first time that the effect of SUA on macrophages has been analyzed. Uric acid lowering therapy has been associated with an increased risk of gout flares. Our results indicate that one mechanism contributing to the development of gout flares could be the diminution of the local regulatory effect of SUA on macrophage activation.
Pascal E. Br J Rheumatol 1995;34(8):724-6.  Latourte A. Rheumatology 2014;53(11):1920-6.
Disclosure of Interest None declared
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