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Abstract

Objective

To profile monosodium urate monohydrate (MSU) crystal–recruited monocyte inflammatory function during the course of in vivo differentiation, in a murine model of peritoneal MSU crystal–induced inflammation.

Methods

C57BL/6J mice were injected intraperitoneally with MSU crystals, and the peritoneal cells were harvested at different time points. The MSU crystal–recruited monocyte/macrophage population was analyzed for the expression of differentiation and activation markers, cytokine production following MSU crystal restimulation ex vivo and in vivo, expression of NLRP3-associated proteins (ASC, caspase 1) and pro–interleukin-1β (proIL-1β), and phagocytic capacity.

Results

Monocytes recruited 8 hours after MSU crystal stimulation (F4/80lowGr-1int7/4+) exhibited poor phagocytic capacity, expressed low levels of proIL-1β, and failed to produce proinflammatory cytokines in response to MSU crystal restimulation. In the absence of MSU crystal restimulation, differentiating monocytes produced low levels of transforming growth factor β1 ex vivo, and this was abrogated following MSU crystal restimulation. Over time these cells developed a proinflammatory phenotype in vivo, characterized by the production of IL-1β, tumor necrosis factor α, IL-6, CCL2 (monocyte chemotactic protein 1), and CXCL1 (cytokine-induced neutrophil chemoattractant) following ex vivo MSU crystal restimulation, and leading to IL-1β production and cell infiltration following MSU crystal rechallenge in vivo. Proinflammatory function was associated with differentiation toward a macrophage phenotype (F4/80highGr-1–7/4–), an increase in phagocytic capacity, and an increase in the expression of proIL-1β.

Conclusion

MSU crystal–recruited monocytes differentiate into proinflammatory M1-like macrophages in vivo. This proinflammatory macrophage phenotype is likely to play a key role in perpetuating inflammation in gouty arthritis in the presence of ongoing deposition of fresh MSU crystals.