Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis (UC), are chronic and recurrent intestinal inflammatory disorders. Numerous studies have revealed that the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a pivotal role in the pathogenesis of IBD, and inhibition of the NLRP3 inflammasome alleviates colitis in experimental animals. Our previous study showed that C646, an inhibitor of histone acetyltransferase p300, has a protective role in dextran sulfate sodium (DSS)-induced colitis by targeting the NLRP3 inflammasome, making us further study the inhibitors of histone deacetylases (HDACs) in the treatment of colitis. In this study, we have shown that WT161, an inhibitor of HDAC6, exerts a protective role in a colitis model, blocks NLRP3 inflammasome activation, disrupts ASC speck formation, and decreases the expression of NLRP3. This study uncovers a new inhibitor of the NLRP3 inflammasome and suggests its potential application in the treatment of active IBD.
Highlights
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis (UC), are chronic and recurrent intestinal inflammatory disorders (Hodson, 2016)
Histopathological analysis showed that WT161 administration decreased the loss of goblet cells and alleviated disruption of crypt structure and mucosal epithelium (Figure 1E), which was confirmed by the lower histological injury score (Figure 1F)
We evaluated the effect of WT161 on IL-1β and IL-6 in the supernatant culture of colonic explants isolated from dextran sulfate sodium (DSS)-induced colitis mice and activated peritoneal macrophages induced by LPS + DSS
Summary
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis (UC), are chronic and recurrent intestinal inflammatory disorders (Hodson, 2016). The precise pathogenesis of IBD remains unclear, it is widely suggested that genetic-environment-mediated dysregulation of the mucosal immune response contributes to its occurrence. The morbidity and burden of IBD are increasing worldwide (Kaplan, 2015; Kaplan and Ng, 2016). The limitations of drugs currently used for IBD treatment, such as aminosalicylic acid, corticosteroids, biologicals, and immunosuppressive agents (Lamb et al, 2019), have prompted researchers to develop new drugs that are suitable for long-term use with fewer side effects. Small-molecule inhibitors have attracted increasing interest as potential agents for the treatment of IBD
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