NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways

Abstract

SUMMARY Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2-deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways including NF-κB, ERK, and STAT3 are significantly higher in Nod2−/− mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis. Consistent with higher inflammation, there is greater proliferation of epithelial cells in hyperplastic regions of Nod2−/− colons. In vitro studies demonstrate that while NOD2 activates the NF-κB and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-κB and MAPK. Notably, NOD2-mediated downregulation of NF-κB and MAPK is associated with the induction of IRF4. Taken together, NOD2 plays a critical role in the suppression of inflammation and tumorigenesis in the colon via downregulation of the TLR signaling pathways.

NOD2 negatively regulated titanium particle-induced osteolysis in mice

“…33 Also NOD2 was reported to suppress colorectal tumorigenesis via down-regulating the TLR pathways, by induction of IRF4. 34 Yet none of the articles shed light upon the mechanism of NOD2's down-regulation effect.…”

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

“…In a study by Watanabe et al., splenocytes from NOD2 –/– mice, as compared to wild‐type splenocytes, produced more IL‐12 and IL‐18 in response to agonists of TLR2 but not of several other TLRs (whereas TLR‐induced TNF and IL‐10 production was not affected) . In a study by Udden et al., bone marrow‐derived macrophages and DCs from NOD2 –/– mice showed enhanced NF‐κB and MAPK activation along with elevated IL‐1β, IL‐6, and TNF mRNA expression upon LPS and poly‐I:C stimulation in vitro . However, in Crohn's disease patients homozygous for NOD2 null mutations, most studies report unaffected responses to TLR agonists in PBMC …”

“…Studies describing inhibitory effects of MDP on TLR‐induced responses also fall into the transcriptional cross‐regulation category, because MDP has been shown to augment expression of negative regulators of TLR signaling such as IRAK‐M or IRF4 …”

“…37 In a study by Udden et al, bone marrow-derived macrophages and DCs from NOD2 -/mice showed enhanced NF-B and MAPK activation along with elevated IL-1 , IL-6, and TNF mRNA expression upon LPS and poly-I:C stimulation in vitro. 43 However, in Crohn's disease patients homozygous for NOD2 null mutations, most studies report unaffected responses to TLR agonists in PBMC. 15,17,19,44 A summary of descriptive data reviewed above is provided in Tables 1 and 2.…”

Novel insights into microbiome in colitis and colorectal cancer

“…Udden et al recently demonstrated that NOD2 negatively regulates TLR/NF-κB signaling to suppress tumorigenesis (18*). Cohousing and microbiota transfer experiments suggest that the microbiota enhances colitis but appears not to be the major driver of the increased CRC susceptibility observed in Nod2 -/- mice compared to WT mice (18*). Mechanistically, NOD2 induces IRF4 which interacts with MYD88 and TRAF6 to suppress TLR/NF-κB signaling in myeloid cells (18*).…”