Journal
CELL REPORTS
Volume 13, Issue 9, Pages 1922-1936Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.10.040
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Funding
- Crohn's and Colitis Foundation Career Development Award [3711]
- American Cancer Society [IRG-02-196-10]
- Harold C. Simmons Comprehensive Cancer Center (National Cancer Institute/NIH) [P30 CA142543]
- UT Southwestern startup funding
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Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2(-/-) mice are highly susceptible to dextran sodium sulfate- induced colitis that is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2(-/-) mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1 beta and IL-18 production are compromised in Aim2(-/-) mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E. coli burden as well as colitis susceptibility in Aim2(-/-) mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis.
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