NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Immunity (Impact Factor: 21.56). 04/2012; 36(5):742-54. DOI: 10.1016/j.immuni.2012.03.012
Source: PubMed

ABSTRACT In vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-κB, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-κB activity is associated with colonic inflammation and cancer, and we found Nlrp12(-/-) mice were highly susceptible to colitis and colitis-associated colon cancer. Polyps isolated from Nlrp12(-/-) mice showed elevated noncanonical NF-κB activation and increased expression of target genes that were associated with cancer, including Cxcl13 and Cxcl12. NLRP12 negatively regulated ERK and AKT signaling pathways in affected tumor tissues. Both hematopoietic- and nonhematopoietic-derived NLRP12 contributed to inflammation, but the latter dominantly contributed to tumorigenesis. The noncanonical NF-κB pathway was regulated upon degradation of TRAF3 and activation of NIK. NLRP12 interacted with both NIK and TRAF3, and Nlrp12(-/-) cells have constitutively elevated NIK, p100 processing to p52 and reduced TRAF3. Thus, NLRP12 is a checkpoint of noncanonical NF-κB, inflammation, and tumorigenesis.

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Available from: Hans Herfarth, Sep 25, 2015
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    • "In addition, the absence of NLPRP3 led to defective production of the downstream effectors cytokines IL-18 and IL-1β, resulting in increased permeability of the gut epithelium. Compromised epithelial barrier function in both NLRP3 and caspase-1 deficient mice allows bacteria to invade the intestinal lamina propria and mucosa, which accelerates inflammatory responses and leads to chronic intestinal inflammation (75). "
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    ABSTRACT: Nucleotide-binding and oligomerization domain NOD-like receptors (NLRs) are highly conserved cytosolic pattern recognition receptors that play, in combination with toll-like receptors, a critical role in innate immunity and inflammation. These proteins are characterized by a central oligomerization domain termed nucleotide-binding domain, and a protein interaction domain containing leucine-rich repeats. Some NLRs, including NOD1 and NOD2, sense the cytosolic presence of conserved bacterial molecular signatures and drive the activation of mitogen-activated protein kinase and the transcription factor NF-κB. A different set of NLRs induces caspase-1 activation through the assembly of large protein complexes known as inflammasomes. Activation of NLR proteins results in secretion of pro-inflammatory cytokines and subsequent inflammatory responses. The critical role of NLRs in innate immunity is underscored by the fact that polymorphisms within their genes are implicated in the development of several immune-mediated diseases, including inflammatory bowel disease. Over the past few years, the role of NLRs in intestinal homeostasis has been highlighted, however the mechanism by which dysfunction in these proteins leads to aberrant inflammation is still the focus of much investigation. The purpose of this review is to systematically evaluate the function of NLRs in mucosal innate immunity and understand how genetic or functional alterations in these components can lead to the disruption of intestinal homeostasis, and the subsequent development of chronic inflammation.
    Frontiers in Immunology 07/2014; 5:317. DOI:10.3389/fimmu.2014.00317
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    • "When treated with AOM/DSS, the resulting increased epithelial proliferation and exacerbated inflammation in Nlrp6−/− mice led to accelerated outgrowth of colonic cancer (16). In addition to NLRP6, loss of NLR family members NOD1, NOD2, NLRP3, NLRC4, and NLRP12 has resulted in similar exacerbated colitis and accelerated rates of cancer (19–24). Together, results from these gut studies suggest NLRs and their associated inflammasome components are essential for controlling wound repair responses and preventing transformative events and unwarranted epithelial proliferation early in potentially neoplastic settings (20). "
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    ABSTRACT: It is believed the immune system can contribute to oncogenic transformation especially in settings of chronic inflammation, be activated during immunosurveillance to destroy early neoplastic cells before they undergo malignant outgrowth, and finally, can assist growth of established tumors by preventing clearance, remodeling surrounding tissue, and promoting metastatic events. These seemingly opposing roles of the immune system at the different stages of cancer development must all be mediated by innate signaling mechanisms that regulate the overall state of immune activation. Recently, the cytosolic nod-like receptor (NLR) pathway of innate immunity has gained a lot of attention in the tumor immunology field due to its known involvement in promoting inflammation and immunity, and conversely, in regulating tissue repair processes. In this review, we present all the current evidence for NLR involvement in the different stages of neoplasia to understand how a single molecular pathway can contribute to conflicting immunological interactions with cancer.
    Frontiers in Immunology 04/2014; 5:185. DOI:10.3389/fimmu.2014.00185
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    • "Using the AOM/DSS model of CAC, Nlrp12−/− mice were shown to develop increased inflammation and tumorigenesis (66, 68). Colon histopathology revealed significant epithelial cell damage and loss of barrier integrity in these animals, which resulted in increased pro-inflammatory cytokine and chemokine production (66, 68). These animals eventually develop extensive pre-cancerous lesions, which result in significantly increased areas of hyperplasia, dysplasia, and adenocarcinoma (66, 68). "
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    ABSTRACT: Aberrant inflammation is an enabling characteristic of tumorigenesis. Thus, signaling cascades that alter inflammatory activation and resolution are of specific relevance to disease pathogenesis. Pattern recognition receptors (PRRs) are essential mediators of the host immune response and have emerged as critical elements affecting multiple facets of tumor pathobiology. The nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins are intracellular PRRs that sense microbial and non-microbial products. Members of the NLR family can be divided into functional sub-groups based on their ability to either positively or negatively regulate the host immune response. Recent studies have identified a novel sub-group of non-inflammasome forming NLRs that negatively regulate diverse biological pathways associated with both inflammation and tumorigenesis. Understanding the mechanisms underlying the function of these unique NLRs will assist in the rationale design of future therapeutic strategies targeting a wide spectrum of inflammatory diseases and cancer. Here, we will discuss recent findings associated with this novel NLR sub-group and mechanisms by which these PRRs may function to alter cancer pathogenesis.
    Frontiers in Immunology 04/2014; 5:169. DOI:10.3389/fimmu.2014.00169
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