NOD2-mediated downregulation of the TLR pathways contributes to protection against colitis and colorectal tumorigenesis

Abstract

Abstract NOD-like receptor family member NOD2, which activates the NF-kB and MAPK signaling pathways in response to the bacterial cell wall component MDP, is the first identified inflammatory bowel disease (IBD) susceptibility gene. IBD is a risk factor for colorectal tumorigenesis. However, the role of NOD2 in colorectal tumorigenesis has not been studied adequately and the precise mechanism of NOD2-mediated protection against IBD is elusive. We studied the role of NOD2 in colorectal tumorigenesis using azoxymethane plus dextran sulfate sodium-induced colorectal tumorigenesis in mice. We found that Nod2-deficient mice are highly susceptible to colorectal tumorigenesis with increased tumor burden as compared to wild-type mice. Interestingly, increased tumorigenesis in Nod2−/− mice was independent of gut microbial composition. Increased tumorigenesis in Nod2-deficient mice was associated with higher inflammatory responses and activation of the inflammatory signaling pathways, such as NF-kB, ERK, and STAT3. Consistently, in vitro studies demonstrate that while NOD2 activates NF-kB and ERK in response to MDP, it inhibits TLR-mediated activation of NF-kB and ERK, and production of inflammatory mediators. Notably, NOD2-mediated downregulation of TLR signaling pathways is independent of MDP-mediated activation of NOD2. We further explored the underlying mechanism of NOD2-mediated downregulation of TLR signaling and revealed that NOD2 induces IRF4 which negatively regulates TLR-NF-kB signaling axis. Taken together, this study therefore shed light on a novel function of NOD2 which may be implicated in genetic association of NOD2 mutations with IBD and colorectal cancer.