The NOD-Like Receptor NLRP12 Attenuates Colon Inflammation and Tumorigenesis

Abstract

SUMMARY NLRP12 is a member of the intracellular Nod-like receptor (NLR) family that has been suggested to down-regulate the production of inflammatory cytokines, but its physiological role in regulating inflammation has not been characterized. We generated mice deficient in Nlrp12 and studied its role in inflammatory diseases such as colitis and colorectal tumorigenesis. We show that Nlrp12-deficient mice are highly susceptible to colon inflammation and tumorigenesis, which is associated with increased production of inflammatory cytokines, chemokines and tumorigenic factors. Enhanced colon inflammation and colorectal tumor development in Nlrp12-deficient mice are due to a failure to dampen NF-κB and ERK activation in macrophages. These results reveal a critical role for NLRP12 in maintaining intestinal homeostasis and providing protection against colorectal tumorigenesis.

Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure

“…Collectively, these studies showed that, when compared with WT mice, Nlrp12 2/2 mice exhibited increased susceptibility to acute colitis as well as to colitis-associated tumorigenesis, and had increased pro-inflammatory cytokine production and increased NF-k B-dependent signalling molecules (Allen et al, 2012b;Zaki et al, 2011). These data support early in vitro findings indicating that NLRP12 negatively regulates non-canonical NF-k B signalling and the related chemokines CXCL12 and CXCL13 .…”

Epithelial NAIPs protect against colonic tumorigenesis

“…In other cases, noninflammasome-mediated factors were found to protect mice against CAC development. For example, NLRP12 was protective against colonic inflammation and tumorigenesis by dampening NF-B and ERK activation in macrophages (Zaki et al, 2011). However, several discrepancies also exist, as illustrated by domains appeared to be necessary for NLRC4 inflammasome formation and activation of caspase-1 (Kofoed and Vance, 2011).…”

“…Several Nod-like receptors (NLRs) have previously been implicated in colon inflammation and tumorigenesis, mostly in protective roles (Allen et al, 2010;Hu et al, 2010;Chen et al, 2011;Elinav et al, 2011;Zaki et al, 2011;Carvalho et al, 2012). In some cases, this has been attributed to reduced inflammasomemediated release of IL-18, which is protective for the colonic epithelium (Allen et al, 2010;Dupaul-Chicoine et al, 2010).…”

“…However, whether they act as IAPs is controversial. Additionally, NAIPs belong to the NLR family, and several NLRs are protective in colonic inflammation and tumorigenesis, through a variety of mechanisms (Allen et al, 2010;Hu et al, 2010;Chen et al, 2011;Elinav et al, 2011;Zaki et al, 2011;Carvalho et al, 2012). Naip1-6 fl/fl and Naip1-6 / mice (nonlittermates) were challenged in a CAC model with administration of the carcinogen azoxymethane (AOM; 10 mg/kg) followed by three cycles of dextran sulfate sodium (DSS; 2.5% wt/vol) to induce colitis and accelerate tumorigenesis.…”

Expression regulation and function of NLRC5

“…It functions asYersinia pestis recognition and inflammasome formation for IL-1b and IL-18 maturation for host defense. Meanwhile, it also suppresses colon inflammation and tumorigenesis through negatively regulating the canonical or non-canonical NF-κB signaling (Zaki et al, 2011;Allen et al, 2012;Vladimer et al, 2012). NLRP7 forms infl ammasome during recognition of microbial lipopeptides in human macrophages (Khare et al, 2012).…”