Epithelial NAIPs protect against colonic tumorigenesis

Inflammasomes of the intestinal epithelium

“…In studies by Hu et al [12] and Allam et al [13], increased tumor load upon NLRC4 or NAIP1-6 deletion appeared independent of inflammation, as determined by weight loss, pathology scoring, and proinflammatory cytokine measurement, and was consistent with an epitheliumintrinsic effect. In line with this finding, NAIP-dependent tumor suppression was also evident in an AOM-only model of CRC, where tumor development occurs independently of chronic inflammation [13].…”

“…Bone marrow transfer and cell fractionation experiments indicated the significance of epithelial NLRC4 [12], although this remains controversial since another report indicated an NLRP3-dependent myeloid cell mechanism in caspase-1-dependent CAC suppression [30]. In the same AOM/DSS model, mice lacking NAIP1-6 globally, or specifically in IECs, had an elevated tumor load, whereas NAIP deletion in myeloid cells had little effect [13]. In studies by Hu et al [12] and Allam et al [13], increased tumor load upon NLRC4 or NAIP1-6 deletion appeared independent of inflammation, as determined by weight loss, pathology scoring, and proinflammatory cytokine measurement, and was consistent with an epitheliumintrinsic effect.…”

“…It is well established that NLRC4 is critical for pathogen restriction by phagocytes in the gut lamina propria and elsewhere [7][8][9]. Interestingly, recent studies have highlighted the role of NAIP(s) and NLRC4 within IECs as a sentinel system that responds to diverse insults such as enteropathogenic bacteria onslaught [10,11] and carcinogen exposure [12,13]. NLRC4 triggering of downstream defenses restricts mucosal pathogen loads, destructive pathology, systemic bacterial translocation, and intestinal tumor formation.…”

“…Removal of AOM-affected IECs appears crucial in preventing tumor onset, as exemplified by the high tumor burden in IEC-specific p53-knockout mice, which fail to induce IEC apoptosis following AOM exposure [31]. Notably, the epithelium in NAIP-deficient mice showed a blunted acute response towards AOM, including reduced levels of phosphorylated p53 and apoptotic IECs, as well as elevated prosurvival signal transducer and activator of transcription 3 (STAT3) pathway signaling [13]. It thus appears likely that elevated tumor loads in NAIP1-6-deficient animals originates in a failure to remove tumor-initiating cells during onset of tumorigenesis.…”

“…Carcinogen exposure and chronic inflammation promote emergence of adenomas in the colonic epithelium and subsequent colorectal carcinoma (CRC) development. Two reports have shown that epithelial NLRC4 [12] and NAIPs [13] suppress colon tumorigenesis. Both Nlrc4 À/À and caspase-1/11 À/À mice displayed markedly increased tumor loads in the azoxymethane plus dextran sodium sulfate (AOM/DSS) model of colitis-associated cancer (CAC).…”