Inflammasome activation has an important role in the development of spontaneous colitis

Abstract

Inflammatory bowel diseases (IBD) are characterized for dysregulated intestinal inflammation. Conflicting reports have shown that activation of inflammasome could promote or decrease intestinal inflammation in an acute colitis model, whereas the involvement of inflammasome activation in chronic colitis is poorly understood. In this study, we investigated the role of inflammasome activation in the development of chronic intestinal inflammation by utilizing IL-10 knockout (KO) mouse as an animal model, which develops chronic colitis resembling human IBD. We demonstrate the causative link between inflammasome activation and the development of chronic intestinal inflammation. Our results show that mature IL-1β protein levels were significantly increased in all colon sections from IL-10 deficient mice compared with that of wild type mice. We found that inhibition of inflammasome activities with IL-1 receptor antagonist or caspase 1 inhibitors suppressed IL-1β and IL-17 production from inflamed colon explants. Furthermore, blocking inflammasome activation with caspase-1 inhibitor in vivo significantly ameliorated the spontaneous colitis in IL-10 KO mice. Together, these observations demonstrate that inflammasome activation promotes the development of chronic intestinal inflammation.

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

“…This is shown in studies of mice with abnormalities of IL-10 production or signaling, where IL-10 has been shown to have a profound inhibitory effect on NLRP3 inflammasome activity; therefore, the absence of IL-10 leads to increased IL-1β production (27). In these studies, it has been shown that IL-10-KO and IL-10R-KO mice exhibit increased NLRP3 inflammasome activity and that an NLRP3 inflammasome inhibitor, such as glyburide or caspase-1 inhibitor, ameliorates colitis occurring in such mice (28,29). In addition, in related studies, it has been shown that blockade of IL-10 signaling causes colitis in TLR5-KO mice attributable to IL-1β, since it does not occur in TLR5/IL-1βR double-KO mice (30).…”

Heterogeneity of subordination of the IL-18/IFN-γ axis to caspase-1 among patients with Crohn's disease

“…Interestingly, a very recent report emphasizes the important role of the inflammasomecaspase-1 pathway in driving the progression of inflammation in the IL10-deficient mouse model of enterocolitis. 32 In fact, in this model, caspase-1 inhibition had a strong beneficial effect. However, the IBD mimicry of this model is very limited.…”

Tr1 Cells, but Not Foxp3+ Regulatory T Cells, Suppress NLRP3 Inflammasome Activation via an IL-10–Dependent Mechanism

“…Recently, two studies found that mice lacking IL-10 have significantly elevated inflammasome activation and IL-1b production, resulting in severe colitis (37) or Ag-induced arthritis (39). However, IL-10 knockout mice also have increased production of other proinflammatory cytokines that could contribute to inflammasome activation as much as the lack of macrophage exposure to IL-10.…”