Control of Intestinal Homeostasis, Colitis, and Colitis-Associated Colorectal Cancer by the Inflammatory Caspases

Department of Biochemistry, McGill University, Quebec, Canada.
Immunity (Impact Factor: 21.56). 03/2010; 32(3):367-78. DOI: 10.1016/j.immuni.2010.02.012
Source: PubMed

ABSTRACT Inflammatory caspases are essential effectors of inflammation and cell death. Here, we investigated their roles in colitis and colorectal cancer and report a bimodal regulation of intestinal homeostasis, inflammation and tumorigenesis by caspases-1 and -12. Casp1(-/-) mice exhibited defects in mucosal tissue repair and succumbed rapidly after dextran sulfate sodium administration. This phenotype was rescued by administration of exogenous interleukin-18 and was partially reproduced in mice deficient in the inflammasome adaptor ASC. Casp12(-/-) mice, in which the inflammasome is derepressed, were resistant to acute colitis and showed signs of enhanced repair. Together with their increased inflammatory response, the enhanced repair response of Casp12(-/-) mice rendered them more susceptible to colorectal cancer induced by azoxymethane (AOM)+DSS. Taken together, our results indicate that the inflammatory caspases are critical in the induction of inflammation in the gut after injury, which is necessary for tissue repair and maintenance of immune tolerance.

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Available from: Maya Saleh, Sep 29, 2015
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    • "Several groups, using a common acute and chronic epithelial injury colitis mouse model based on the administration of DSS, reported an exacerbated disease severity in mice deficient in caspase-1, NLRP3, and NLPR6. These NLPRs are correlated with lower IL-1í µí»½ and IL-18 production during colitis [89] [90] [91] [92]. Interestingly, NLPR6-deficient mice have an altered gut microbiota (colitogenic bacteria), which together with the exacerbated colitis phenotype can be transferred to cohabitating WT mice. "
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    ABSTRACT: The commensal microbiota is in constant interaction with the immune system, teaching immune cells to respond to antigens. Studies in mice have demonstrated that manipulation of the intestinal microbiota alters host immune cell homeostasis. Additionally, metagenomic-sequencing analysis has revealed alterations in intestinal microbiota in patients suffering from inflammatory bowel disease, asthma, and obesity. Perturbations in the microbiota composition result in a deficient immune response and impaired tolerance to commensal microorganisms. Due to altered microbiota composition which is associated to some inflammatory diseases, several strategies, such as the administration of probiotics, diet, and antibiotic usage, have been utilized to prevent or ameliorate chronic inflammatory diseases. The purpose of this review is to present and discuss recent evidence showing that the gut microbiota controls immune system function and onset, development, and resolution of some common inflammatory diseases.
    Research Journal of Immunology 09/2014; 2014:689492. DOI:10.1155/2014/689492
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    • "Moreover, the interaction between ER stress pathways and inflammasomes is still yet to be established. Several studies showed that mice deficient for inflammasome components including NLRP3, ASC, and caspase-1 were highly susceptible to acute colitis induced by DSS, indicating the protective role of inflammasome in acute colitis (Allen et al., 2010; Dupaul-Chicoine et al., 2010; Hirota et al., 2011). However, Bauer et al. (2010) showed that that defective in NLRP3 inflammasome protected mice from DSS-induced acute colitis, indicating that inflammasomes contribute to the development of colitis. "
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    ABSTRACT: As an adaptive response to the overloading with misfolded proteins in the endoplasmic reticulum (ER), ER stress plays critical roles in maintaining protein homeostasis in the secretory pathway to avoid damage to the host. Such a conserved mechanism is accomplished through three well-orchestrated pathways known collectively as unfolded protein response (UPR). Persistent and pathological ER stress has been implicated in a variety of diseases in metabolic, inflammatory, and malignant conditions. Furthermore, ER stress is directly linked with inflammation through UPR pathways, which modulate transcriptional programs to induce the expression of inflammatory genes. Importantly, the inflammation induced by ER stress is directly responsible for the pathogenesis of metabolic and inflammatory diseases. In this review, we will discuss the potential signaling pathways connecting ER stress with inflammation. We will also depict the interplay between ER stress and inflammation in the pathogenesis of hepatic steatosis, inflammatory bowel diseases and colitis-associated colon cancer.
    Frontiers in Genetics 07/2014; 5:242. DOI:10.3389/fgene.2014.00242
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    • "In vitro studies originally demonstrated that transient transfection of NLRP12 and ASC induces inflammasome formation, as well as transcription of an NF-κB reporter construct, suggesting that NLRP12 was an inflammasome forming NLR, and promoted caspase-1 activation and production of IL-1β, in addition to being a positive regulator of NF-κB signaling (72). Evidence for the involvement of NLRP12 in induction of inflammasome formation are mostly based on in vitro studies; ex vivo studies have evaluated NLRP12 inflammasome formation using NLRP3 deficient mice, and have shown that this NLR actually is not able to regulate formation of either IL-1β and IL-18 (73–75, 86–90). "
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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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