4.8 Article

Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1307575110

关键词

colon cancer; microflora; ASC

资金

  1. Cancer Research Institute
  2. Israel-US Educational Foundation
  3. American Physicians for Medicine in Israel Foundation
  4. Deutsche Forschungsgemeinschaft [SFB841]
  5. Crohn's and Colitis Foundation of America fellowship
  6. National Institutes of Health [K08AI085038, UL1 RR024139]
  7. Howard Hughes Medical Institute
  8. United States-Israel Binational Foundation

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The microbiota is pivotal in the pathogenesis of inflammatory bowel disease (IBD)-associated inflammation-induced colorectal cancer (CRC), yet mechanisms for these effects remain poorly characterized. Here, we demonstrate that aberrant inflammasome-induced microbiota plays a critical role in CRC development, where mice deficient in the NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome feature enhanced inflammation-induced CRC formation. Intriguingly, WT mice cohoused either with inflammasome-deficient mice or with mice lacking IL-18 feature exacerbated inflammation-induced CRC compared with singly housed WT mice. Enhanced tumorigenesis is dependent on microbiota-induced chemokine (C-C motif) ligand 5 (CCL5)-driven inflammation, which in turn promotes epithelial cell proliferation through local activation of the IL-6 pathway, leading to cancer formation. Altogether, our results mechanistically link the altered microbiota with the pathogenesis of inflammation-induced CRC and suggest that in some conditions, microbiota components may transfer CRC susceptibility between individuals.

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