NOD takes its toll but stays in the CARDs in Crohn’s disease

  • F. Luft
  • Published 2005 in Journal of Molecular Medicine

Abstract

Braat et al. [1] reported on nucleotidebinding oligomerization domain (NOD) 2 and toll-like receptor (TLR) 4 mutations in patients with Crohn’s disease. They found that the R702W and 1007fs NOD2 alleles as well as the A299G TLR4 allele were significantly more common in patients with Crohn’s disease compared to normal controls or patients with ulcerative colitis. Braat et al. [1] then performed microarrays after stimulating monocyte-derived dendritic cells from homozygous TLR4 and NOD2 mutant patients with lipopolysaccharides and peptidoglycans. They were able to demonstrate a distinct phenotype in these cells compared to controls. Their work adds to the growing body of evidence implicating NOD2 and TLR4 in Crohn’s disease. A brief review of putative mechanisms is in order. Inflammatory bowel diseases occur in areas of the gastrointestinal tract with the highest numbers of luminal bacteria [2]. The distal ileum contains 10–10 bacteria, mostly anaerobic, per gram, whereas the colon has 10–10 bacteria per gram of luminal content. The hypothesis that inflammatory bowel disease is a sequel to an overly aggressive cell-mediated immune response to normal, endogenous enteric bacteria in a genetically susceptible individual has become a favorite notion. Individual membrane-bound TLRs (TLR1–TLR9) recognize a different bacterial product. For instance, TLR2 recognizes peptidoglycans, whereas TLR4 recognizes lipopolysaccharides. When a bacterial adjuvant binds to these receptors, nuclear factor-.B (NF-.B), a central signaling pathway that mediates the transcription of proinflammatory molecules, is activated. NOD2 belongs to the CATERPILLER [caspase recruitment domain (CARD), transcription enhancer, r(purine)-binding, pyrin, lots of leucine repeats] family of proteins and is also known as CARD15. Normally, intestinal epithelial cells do not constitutively express NOD2 and TLR4; however, the proteins are upregulated in inflammatory bowel disease by proinflammatory cytokines such as tumor necrosis factor alpha (TNF-!) through an NF-.B-dependent mechanism. Polymorphisms in NOD2 that are said to decrease NF-.B responses to peptidoglycans via TLR2 have been identified. Moreover, another NOD2 mutation leads to a truncated protein that defectively clears Salmonella infecting epithelial cells. Mutations in NOD2 occur in up to a quarter of patients with Crohn’s disease. The NOD2 mutations, apparently, are far less common in Japanese, Korean, and Chinese patients. However, Crohn’s disease is a complex genetic condition. Mutations in TLR4, CD14, and other genes have been described [3]. Certain bacterial infections, most notably infections with Mycobacterium avium paratuberculosis, have been implicated in Crohn’s disease. In ruminants, this bacterium causes Johne’s disease, which resembles Crohn’s disease, and is not killed by pasteurization of milk. Naser et al. [4] found the organism in DNA from buffy coats and successfully cultured the bacterium from the blood of patients with Crohn’s disease. These findings raise the possibility that antibiotics might be helpful. Probiotics are commensal bacterial species with beneficial physiologic or therapeutic activities. This approach has also generated interest. In any event, normal, nonpathogenic, enteric bacteria induce and perpetuate chronic intestinal inflammation in genetically susceptible hosts with defective immunoregulation, bacterial clearance, or mucosal barrier dysfunction. Optimal treatments have not yet been identified. The observation that NOD2 mutations result in massive bowel inflammation if they decrease NF-.B activation is counterintuitive. Netea et al. [5] found that NOD2 mutation leads to a defective release of interleukin (IL) 10 from blood mononuclear cells after stimulation with TLR2 ligands such as peptidoglycans. Thus, NOD2 dysfunction results in the release of a proinflammatory cytokine. Watanabe et al. [6] relied on NOD2 gene-deleted mice and showed that intact NOD2 signaling inhibited TLR2-driven activation of NF-.B, particularly of the c-Rel subunit. NOD2 deficiency increased TLR2-mediated NF-.B activation and enhanced TH1 cell responses. O’Neill [7] summed up this mechanism. TLR2 senses peptidoglycans, which can be incorporated into antigen-presenting dendritic cells. Once incorporated, peptidoglycans are broken down Clinical Implications

DOI: 10.1007/s00109-005-0686-9

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Cite this paper

@article{Luft2005NODTI, title={NOD takes its toll but stays in the CARDs in Crohn’s disease}, author={F. Luft}, journal={Journal of Molecular Medicine}, year={2005}, volume={83}, pages={577-578} }