Background/Purpose: Gout is the most common metabolic disease in which monosodium urate (MSU) crystals form and deposit in the joints and soft tissues of patients. While several lines of evidence support the importance of MSU-induced macrophage activation in the inflammatory response in gout, the mechanism remains unclear. Recent studies implicate CCN3 matricellular signaling protein as emerging player in the regulation of inflammation, reactive oxygen species production and angiogenesis. Additional data suggest that CCN3 regulates macrophage polarization and foam cell formation in diabetes and atherosclerosis. However, information regarding the role of CCN3 in gout remains unclear. Therefore, the objective of this investigation was to decipher the role of CCN3 in the pathogenesis of gout.

Methods: A total of 41 gout patients and 41 healthy control subjects, matched for age and sex ratio, were enrolled. PBMCs and serum were harvested and subjected to real-time PCR and ELISA analysis. MSU-induced peritonitis was conducted in LysM-Cre CCN3^fl/fl mice with a macrophage-selective deletion of CCN3. In addition, the IL-1β production of bone marrow derived macrophage (BMM) and peritoneal macrophage with CCN3 deletion or not were investigated.

Results: Levels of CCN3 were predominantly increased in gout patients when compared to healthy controls. Furthermore, the sera CCN3 levels showed a positive correlation with inflammatory response protein CRP, while no significant correlation with lipids level were observed. To further address the role CCN3 in the pathogenesis of gout, MSU-induced peritonitis was conducted in LysM-Cre CCN3^fl/fl mice with a macrophage-selective deletion of CCN3. As expected, LysM-Cre CCN3^fl/fl mice showed a decreased cell infiltration in the peritoneal cavity. In addition, decreased levels of IL-1β in the peritoneal lavage fluid and caspase1 activity in peritoneal macrophage were observed in LysM-Cre CCN3^fl/fl mice. Similarly, bone marrow derived macrophage (BMM) and peritoneal macrophage with CCN3 deletion showed an impaired caspase1 activation and IL-1β production in vitro.

Conclusion: These results indicate that CCN3 in macrophage  plays a critical role in the development of MSU-induced inflammation.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/ccn3-regulates-macrophage-function-in-msu-induced-inflammation/