A Novel Benzo[d]Imidazole Derivates Prevents The Development Of DSS-induced Experimental Colitis Via Inhibition Of NLRP3 Inflammasome

Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disease (IBD) characterized by abdominal pain, rectal bleeding, diarrhea and malnutrition. Pathological lesions associated with UC are restricted to the mucosal layer of the gut lumen. The exact cause of UC remains undetermined. UC not only impairs patients’ quality of life, but also contributes to the risk of colon cancer. Generally, treatment of inflammatory bowel disease depends on anti-inflammation and regulation of immunoreaction. Most of the time, immunosuppressants such as salicylic acids, prednisone, CsA, FK506, TNF inhibitor may be required to control the symptoms. However, they also have potential side effects including steroid dependence, and serious infections. Therefore, novel strategies with fewer adverse effects are desperately needed.In the first part, we summarized the advance of inflammasomeand the relationship between NLRP3 inflammasome and inflammatory disease. NLRP3 inflammasome has a role in the pathogenesis of inflammatory disease. It seems that some of these can be treated by targeting NLRP3 inflammasome.In the second part, we demonstrated Fclla-2 attenuated the severity of DSS-induced colitis in mice. First of all, we screened a series of compounds by assaying their inhibition rate of IL-1β which was produced by LPS primed ATP activated THP-1 cells. Generally, intragastric administration of Fc11a-2 at the dose of 10-30 mg/kg significantly recovered the decrease in body weights, and the diarrhea in colitis mice was also notably alleviated. Meanwhile, Fc11a-2 administration markedly prevented the inflammatory damage of colons, characterized by reduction of inflammatory cytokines both in the mRNA and protein level and suppression of MAPK、STAT1 and NF-κB signaling pathway. What’s more, Fc11a-2 administration the infiltration of macrophages and the activation of caspase-1 in peritoneal macrophage cells. These findings showed the beneficial effect of Fc11a-2 on DSS-induced colitis.In the third part, we further investigated the mechanism that Fclla-2 inhibited inflammasome activation by suppressing the activation of caspase-1 and thus the activation of IL-1β and IL-18. Fclla-2 had very modest effect on the activation of NF-κB and the reduction of mitochondrial membrane potential induced by LPS and ATP, respectively. In our further study, we found Fclla-2 inhibited the autocleavage the caspase-1 and in turn inhibiting NLRP3 activation.In summary, our work explored a novel therapeutic strategy for ulcerative colitis by targeting NLRP3 inflammasome with a small molecular compound Fclla-2. Besides, we explored the mechanism by which Fc11a-2 inhibited the activation of NLRP3 inflammasome. These results provide not only a new idea for development of colitis therapeutic drug, but also a useful reference for the role of NLRP3 inflammasome in the pathogenesis of IBD.