Summary Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators were largely intact in Aim2-deficient mice, however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with wild-type healthy mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.

Background: C. rodentium and E. coli induce noncanonical Nlrp3 inflammasome activation through caspase-11. Results: TLR4-TRIF are important for caspase-11 expression, caspase-1 activation, and downstream IL-1␤ and IL-18 production. Conclusion: TLR4-TRIF axis plays an important role in the up-regulation of caspase-11 and activation of noncanonical inflammasome. Significance: Our study identifies novel molecules upstream of caspase-11 that are involved in activation of noncanonical inflammasome.

Background:Citrobacter rodentium is an enteric bacterial pathogen of mouse intestinal tract. Results: Mice lacking Nlrp3, Nlrc4, and caspase-1 are hypersusceptible to C. rodentium-induced gastrointestinal inflammation. Conclusion: The Nlrp3 and Nlrc4 inflammasomes play a critical role in host defense against enteric infection caused by C. rodentium. Significance: Our study establishes a critical role of inflammasomes in host defense against Citrobacter rodentium infection.

STING is a cytoplasmic innate immune sensor for cyclic dinucleotides, which also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. Although STING has important functions in the host defense against pathogens and autoimmune diseases, its physiological role in cancer is unknown. Here, we show that STING-deficient mice are highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibit elevated intestinal damage and overt proliferation during early stages of tumorigenesis. Moreover, STING-deficient mice fail to restrict activation of the NF-κB and STAT3 signaling pathways, which leads to increased levels of the pro-inflammatory cytokines IL-6 and KC. Our results, therefore, identified an unexpected and important role for STING in mediating protection against colorectal tumorigenesis.