Hu, B. et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc. Natl. Acad. Sci. USA 107, 21635-21640

Department of Immunobiology, Section of Comparative Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2010; 107(50):21635-40. DOI: 10.1073/pnas.1016814108
Source: PubMed


Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1-deficient (Casp1(-/-)) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1-deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.

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Available from: Richard A Flavell, Oct 02, 2015
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    • "Caspase-1 / and Nlrc4 / mice have also been reported to have increased tumorigenesis in the AOM/DSS CAC model (Hu et al., 2010); however, another study reported no role for NLRC4 (Allen et al., 2010). The study by Hu et al. (2010), demonstrated that, similar to Naip1-6 / mice, Nlrc4 / and Caspase-1 / mice display an epithelialintrinsic increase in tumorigenesis that was not dependent on IL-1 or IL-18. Their results differ to the Naip1-6 / phenotype in that Nlrc4 / and Caspase-1 / mice have equivalent levels of DSS-induced colitis compared with WT counterparts (which we saw similarly for Nlrc4 / in our laboratory; unpublished data), whereas Naip1-6 / mice have decreased susceptibility. "
    Journal of Experimental Medicine 03/2015; DOI:10.1084/jem.30240474 · 12.52 Impact Factor
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    • "Specifically, bone marrow chimera experiments revealed that the protective effect of NLRC4 is dependent on its elevated expression in epithelial crypts, but not in intestinal stromal cells (105). Another study supports an intrinsic epithelial cell effect leading to enhanced tumorigenesis in the absence of NLRC4 (84). In fact, this study showed that NLRC4 mice have a higher frequency of tumors in the AOM–DSS model compared to wild-type mice. "
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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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    • "Despite this important information, the molecular signatures of agonists recognized by NAIP/NLRC4 inflammasomes still require further study. Moreover, NLRC4 has been associated with host resistance against a mucosal Candida albicans infection (115) and in a colitis-associated colorectal cancer (CAC) model (116, 117). Interestingly, in both cases, NLRC4 seems to exert a protective role in non-hematopoietic compartments. "
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    ABSTRACT: Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are acti-vated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically associate with NLRC4 to form an inflammasome complex able to recruit and activate pro-caspase-1. NAIP5 and NAIP6 sense flagellin, component of flagella from motile bacteria, whereas NAIP1 and NAIP2 detect needle and rod components from bacterial type III secretion systems, respectively. Active caspase-1 mediates the maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18, and is responsible for the induction of pyroptosis, a pro-inflammatory form of cell death. In addition to these well-known effector mechanisms, novel roles have been described for NAIP/NLRC4 inflammasomes, such as phagosomal maturation, activation of inducible nitric oxide synthase, regulation of autophagy, secretion of inflammatory media-tors, antibody production, activation of T cells, among others. These effector mechanisms mediated by NAIP/NLRC4 inflammasomes have been extensively studied in the context of resistance of infections and the potential of their agonists has been exploited in therapeutic strategies to non-infectious pathologies, such as tumor protection. Thus, this review will discuss current knowledge about the activation of NAIP/NLRC4 inflammasomes and their effector mechanisms.
    Frontiers in Immunology 07/2014; 5. DOI:10.3389/fimmu.2014.00309
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