Lala S, Ogura Y, Osborne C, et al. Crohn's disease and the NOD2 gene: a role for paneth cells

University of Michigan, Ann Arbor, Michigan, United States
Gastroenterology (Impact Factor: 16.72). 07/2003; 125(1):47-57. DOI: 10.1016/S0016-5085(03)00661-9
Source: PubMed

ABSTRACT The NOD2 gene, which is strongly associated with susceptibility to Crohn's disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LPS), inducing cellular activation. However, the mechanisms by which NOD2 mutations cause terminal ileitis are unknown, and NOD2 is expressed most highly by peripheral blood monocytes, which are distributed ubiquitously and readily respond to LPS via cell-surface receptors. Paneth cells on the other hand, are most numerous in the terminal ileum, are critically important in enteric antibacterial defense, and respond to LPS through as yet undefined pathways. We therefore determined if these specialized intestinal epithelial cells also expressed the NOD2 gene.
In situ hybridization, immunohistochemistry, and laser-capture microdissection were used to determine RNA and protein expression in tissue sections, and real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to quantitate gene expression in intestinal epithelial cells and peripheral blood mononuclear cells.
NOD2 was detected readily in monocytes, but not in mature macrophages in the lamina propria or within granulomas, and levels declined as monocytes differentiated into macrophages in vitro, so that Caco-2 cells expressed more NOD2 mRNA than macrophages. NOD2 mRNA was enriched in crypts compared with villi, and in situ, Paneth cells were the most prominent cells expressing NOD2 in normal and CD-affected intestinal tissue, where they also strongly expressed tumor necrosis factor alpha (TNFalpha) RNA.
The NOD2 gene product is most abundant in Paneth cells in the terminal ileum, which could therefore play a critical and hitherto unrecognized role in the pathogenesis of NOD2-associated CD.

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    • "Central in this discussion is the Paneth cell and its products. Paneth cells express high levels of NOD2, a pattern recognition receptor whose genetic variants have been associated with IBD [101]. This has led to the suggestion that NOD2-as- sociated susceptibility to CD is a result of loss a-defensin expression from ileal Paneth cells [102]. "
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    ABSTRACT: Abstract The single-cell thick intestinal epithelial cell (IEC) lining with its protective layer of mucus is the primary barrier protecting the organism from the harsh environment of the intestinal lumen. Today it is clear that the balancing act necessary to maintain intestinal homeostasis is dependent on the coordinated action of all cell types of the IEC, and that there are no passive bystanders to gut immunity solely acting as absorptive or regenerative cells: Mucin and antimicrobial peptides on the epithelial surface are continually being replenished by goblet and Paneth's cells. Luminal antigens are being sensed by pattern recognition receptors on the enterocytes. The enteroendocrine cells sense the environment and coordinate the intestinal function by releasing neuropeptides acting both on IEC and inflammatory cells. All this while cells are continuously and rapidly being regenerated from a limited number of stem cells close to the intestinal crypt base. This review seeks to describe the cell types and structures of the intestinal epithelial barrier supporting intestinal homeostasis, and how disturbance in these systems might relate to inflammatory bowel disease.
    Scandinavian Journal of Gastroenterology 01/2015; 50(1):3-12. DOI:10.3109/00365521.2014.971425 · 2.36 Impact Factor
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    • "Furthermore, some intestinal bacteria rely on NOD2 recognition for activation of innate immune responses, but such recognition is impaired in macrophages harboring CD-associated NOD2 variants (Kim et al., 2011b). Paneth cells that are located in the crypts of the small intestine and secrete antibacterial proteins and peptides such as a-defensins express NOD2 (Lala et al., 2003; Ogura et al., 2003). Notably, CD-associated NOD2 variants confer susceptibility to the development of ileal, but not colonic, lesions, corresponding to the location of Paneth cells (Gasche and Grundtner, 2005). "
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    ABSTRACT: The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6):898-908. DOI:10.1016/j.immuni.2014.12.010 · 21.56 Impact Factor
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    • "While it is generally agreed that myeloid cells may play a role in this respect, it would be important to investigate whether IECs, or more specifically Paneth cells, may secrete significant amounts of inflammatory cytokines in healthy or diseased gut mucosal tissues. This is in fact the case of the preferential secretion by Paneth cells among IECs of TNFα leading to IBD, particularly Chron’s disease, and possibly to cancer, even if this last aspect has not been addressed (97). "
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    ABSTRACT: The observation that cancer often arises at sites of chronic inflammation has prompted the idea that carcinogenesis and inflammation are deeply interwoven. In fact, the current literature highlights a role for chronic inflammation in virtually all the steps of carcinogenesis, including tumor initiation, promotion and progression. The aim of the present article is to review the current literature on the involvement of chronic inflammation in the initiation step and in the very early phases of tumorigenesis, in a type of cancer where adult stem cells are assumed to be the cells of origin of neoplasia. Since the gastrointestinal tract is regarded as the best-established model system to address the liaison between chronic inflammation and neoplasia, the focus of this article will be on intestinal cancer. In fact, the anatomy of the intestinal epithelial lining is uniquely suited to study adult stem cells in their niche, and the bowel crypt is an ideal developmental biology system, as proliferation, differentiation and cell migration are all distributed linearly along the long axis of the crypt. Moreover, crypt stem cells are regarded today as the most likely targets of neoplastic transformation in bowel cancer. More specifically, the present review addresses the molecular mechanisms whereby a state of chronic inflammation could trigger the neoplastic process in the intestine, focusing on the generation of inflammatory cues evoking enhanced proliferation in cells not initiated but at risk of neoplastic transformation because of their stemness. Novel experimental approaches, based on triggering an inflammatory stimulus in the neighbourhood of adult intestinal stem cells, are warranted to address some as yet unanswered questions. A possible approach, the targeted transgenesis of Paneth cells, may be aimed at 'hijacking' the crypt stem cell niche from a status characterized by the maintenance of homeostasis to local chronic inflammation, with the prospect of initiating neoplastic transformation in that site.
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