NLRP3 inhibition leads to impaired mucosal fibroblast function in patients with inflammatory bowel diseases.

The multifactorial pathogenesis of inflammatory bowel diseases (IBD) is only partially understood. The dysregulation of immunological processes in the intestine leads to a persistent inflammation and the proinflammatory milieu results in the excessive production of extracellular matrix (ECM) like collagens and fibronectin. Pathological increase of ECM is associated with intestinal fibrosis and structure remodeling, a severe complication of IBD. The contribution of a hyperactive NLRP3 inflammasome to the development and perpetuation of intestinal inflammation is already known but the exact role of NLRP3 in IBD remains still unclear. We found increased NLRP3 expression in the inflamed intestinal mucosa of IBD patients. Inhibition of the NLRP3 inflammasome resulted in a significant decrease in the secretion of the proinflammatory cytokines IL-1β and IL-18 in blood cells and the bioactive form of mucosal IL-1β in IBD patients. Due to overlapping expression patterns of NLRP3 and IL-1β in classically activated macrophages found in single cell analysis and the detection of NLRP3 in CD163-positive monocytes/macrophages, we identified monocytes/macrophages as the main cell-type involved in the NLRP3 signaling pathway. In addition, expression of the NLRP3 inflammasome in intestinal fibroblasts was found. Inhibition of NLRP3 caused significantly reduced proliferation of intestinal fibroblasts from IBD patients, which was associated with a marked decrease in production of collagen type I and type VI. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.