The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer

TLDR

Colitis‑associated cancer is a major complication of inflammatory bowel disease. The study assessed Nlrp3 and Nlrc4 knockout mice to identify the NLR component involved in colitis and CAC. Using knockout mice and bone‑marrow reconstitution, the authors showed that NLRP3 activity in hematopoietic cells protects against colitis‑associated tumorigenesis. Loss of inflammasome components (Pycard, Casp1, or Nlrp3) worsened colitis and tumor burden with reduced IL‑1β/IL‑18 at tumors, while Nlrc4 deficiency had no effect, demonstrating that the inflammasome, via hematopoietic NLRP3, functions as a tumor suppressor in colitis‑associated cancer.

Abstract

Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1β and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3−/− mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3−/− mice than in Pycard−/− or Casp1−/− animals. No significant differences were observed in disease progression or outcome in Nlrc4−/− mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.