CCN3 aggravates intestinal inflammation in inflammatory colitis through regulating NLRP3 inflammasome in macrophages

Abstract CCN3 is one of member in CCN family that regulates several cellular activities including cell adhesion, proliferation and migration. However, the role of CCN3 in the pathogenesis of inflammatory bowel disease (IBD), an idiopathic intestinal disease characterized by chronic inflammation of the gastrointestinal tract, remains unclear. Herein, we established a DSS induced colitis model that mimic human inflammatory bowel disease by using the CCN3 conditional knock-out mice (LysMCre-ccn3f/f). We found that the mortality and colitis disease score were significantly reduced in LysMCre-ccn3f/f mice, compared to the control group (LysMCre). To further evaluate the contribution of macrophages and neutrophils to the protective effect of CCN3 deletion on colitis, we separately depleted macrophages and neutrophils in these mice before colitis induction. The difference in disease severity between these two groups was abolished after the depletion of macrophages, but not neutrophils, suggesting that CCN3 expression in macrophages plays a critical role in intestinal inflammation. In addition, we found that the production of IL-1b and expression of NLRP3 in LysMCre-ccn3f/f bone marrow-derived macrophages (BMDM) were significantly lower than those in LysMCre, indicating that NLRP3 inflammasome activation may be involved. In conclusion, our data provide a direct evidence that CCN3 may play a role in colitis by regulating NLRP3 inflammasome activation in macrophages.