RAPID CCL2 RELEASE BY MEMBRANE STROMAL CELLS INITIATES MONOSODIUM URATE CRYSTAL-INDUCED MONOCYTE RECRUITMENT IN A PERITONEAL MODEL OF GOUTY INFLAMMATION

Monocyte recruitment is a characteristic feature of the inflammatory response to monosodium urate (MSU) crystals in gout, however the specific cell population(s) responsible for initiating this event is unclear. We therefore investigated the contribution of resident and stromal cell populations to the initiation of MSU crystal-induced inflammatory cytokine and chemokine production in a peritoneal murine model of gout. Depletion of resident macrophages decreased neutrophil infiltration but did not affect MSU crystal-induced monocyte recruitment in vivo despite a significant decrease in overall CCL2 production. Activation of isolated resident peritoneal cells and peritoneal membrane with MSU crystals in vitro indicated that resident peritoneal cells, more specifically resident macrophages, were primarily responsible for the production of the neutrophil chemokine CXCL1, whereas CCL2 was exclusively produced in membrane cultures. Primary culture of membrane mesothelial cells followed by MSU crystal stimulation resulted in CD14-independent CCL2 release from intracellular stores. These findings confirm that MSU crystal-induced neutrophil recruitment is dependent on CXCL1 production by resident macrophages. Conversely, monocyte infiltration may be primarily initiated by the release of low level CCL2 by stromal cells in the surrounding tissue. As such, the synovial tissue in the joint may play a direct role in regulating inflammation in gout.