PAP-1 ameliorates DSS-induced colitis with involvement of NLRP3 inflammasome pathway

Background: Macrophages are a primary type of innate immune cells activated in colitis. Kv1.3 channel is one of the major potassium channels in macrophages. NLRP3 inflammasome is a downstream molecule of Kv1.3 channel. PAP-1, a specific Kv1.3 channel blocker, has been shown to have immune-regulatory effects. Objective: To investigate the effect of PAP-1 on intestinal inflammation in DSS-induced colitis and explore its possible mechanism. Methods: C57BL/6 mice were divided into four groups: normal control group, normal +PAP-1 injection group, DSS model group, DSS model +PAP-1 injection group. Experimental colitis was induced by 5% DSS treatment; mice were injected intraperitoneally with PAP-1 from the first day for 7 consecutive days; then all mice were sacrificed, followed by isolation of colon tissue, peritoneal macrophages and spleen macrophages. The antiinflammatory effects of PAP-1 and the expression levels of Kv1.3, iNOS, pro-IL-1 beta, IL-1 beta and NLRP3 inflammasome were measured. Results: PAP-1 reduced DSS-induced colonic pathological damage, DAI score, MPO activity and levels of IL-1, IL-6, TNF-alpha, IL-18. Compared with the DSS model group, the expression of Kv1.3, iNOS, NLRP3, ASC, caspase-1p20, pro-IL-1 beta and IL-1 beta in colon were decreased in the DSS-induced colitis mice with PAP-1 injection. PAP-1 also reduced the expression of Kv1.3, iNOS, NLRP3, caspase-1p20 and IL-1 beta on macrophages in colitis mice. Conclusion: PAP-1 had protective effects on DSS-induced colitis, which might be ascribed to the regulation of NLRP3 inflammasome pathway. Therefore, we found that PAP-1 was useful as a therapeutic agent in IBD and suggested a potential important role of PAP-1 in NLRP3 inflammasome-associated diseases.