Trends in Microbiology
Volume 14, Issue 10, October 2006, Pages 432-438
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Opinion
NODs in defence: from vulnerable antimicrobial peptides to chronic inflammation

https://doi.org/10.1016/j.tim.2006.08.008Get rights and content

Defensins and cathelicidins are prevalent and essential gastrointestinal cationic antimicrobial peptides (CAPs). However, these defensive peptides are not infallible because certain enteropathogens can overcome their protective function. Furthermore, impaired defensin synthesis has been linked to the occurrence of Crohn's disease (CD), a chronic inflammatory bowel disease. Recently, defective bacterial sensing through NOD1 and NOD2 has been related to reduced defensin production, CD predisposition and susceptibility to enteric infection. Hence, we propose that microbial sensors at the gut interface monitor the levels of these effector peptides, which might function as ’danger’ signals to confer tolerance and alert immunocytes. Further work is required to clarify how gastrointestinal CAPs are regulated and to assess their role in maintaining epithelial homeostasis and triggering adaptive immunity.

Section snippets

Linking inflammatory bowel disease to a vulnerable armoury of cytosolic innate sensors

The digestive mucosa has evolved various immune strategies to tolerate intimate contact with commensals and to prevent pathogenic bacteria from spreading into host tissues. The recognition of foodborne indigenous and pathogenic microbes is an essential barrier function for the survival of insects and mammals. In particular, mammalian resistance to pathogens is mainly conferred by membrane-bound Toll-like receptors (TLRs) [1] and the recently identified family of cytosolic nucleotide-binding

Gastrointestinal antimicrobial peptides: implications for inflammatory disease

Recent reports have shed light on the effector role of CAPs in monitoring gut homeostasis and in the containment of invading microbes because the stem cells that replenish the gut epithelium require continuous antimicrobial protection. The level of CAP expression parallels intestinal development in metazoans, from the immaturity of local defence mechanisms during gestation to bacterial colonization of the gut after birth [12]. In this section, we focus on the NF-κB-dependent and

Hide and seek: when enteric microbes and defensins enter into combat

To circumvent the microbicidal activity of CAPs, microorganisms (generally pathogens) have developed a range of strategies that are reminiscent of those involved in antibiotic resistance [39]. One way to achieve inactivation is to produce proteases, which degrade CAPs; however, in the case of defensins, the intramolecular disulphide bridges render the peptides relatively resistant to enzymatic proteolysis. Another stratagem reduces the net cationic charge of the bacterial envelope to lower its

Host failure to monitor defensins associated with Crohn's disease

Three mutations in the NOD2 gene (namely Arg702Trp, Gly908Arg and the frameshift mutation 1007fs) lead to a predisposition to CD 3, 4. Genotype–phenotype correlations have established that NOD2 mutants are predominantly linked to ileal CD [42]. Both common and rare mutations have been associated with impaired MDP-induced NF-κB activation 5, 7 and cytokine production in peripheral blood monocytes 7, 43, 44, 45. Lala and collaborators recently reported that NOD2 is highly expressed in Paneth

Gastrointestinal antimicrobial peptides: multifaceted molecules

The antimicrobial activity of CAPs seems to be only the ‘tip of the iceberg’ because pleiotropic functions have been attributed to defensins and cathelicidins [53] (Table 1). Both CAPs have the ability to chemoattract immunocytes involved in innate immunity (neutrophils and monocytes or macrophages), adaptive immunity (dendritic cells and T lymphocytes) and allergic or inflammatory reactions (mast cells). Furthermore, hBD-2 might activate the TLR4-dependent signalling pathway in dendritic cells

Concluding remarks

Enteric CAPs have several essential and emerging roles in both the innate and adaptive immunity of the gastrointestinal tract by modulating microbial resistance, angiogenesis and chemotaxis and by promoting the humoral response (Table 1). In particular, release of CAPs into the lumen is thought to protect the mitotically active crypt cells (which renew the epithelial cell monolayer) from colonization by pathogenic microbes. The use of transgenic animals would yield a better understanding of the

Acknowledgements

We are grateful to P. Chavatte for the images of antimicrobial peptides in Figure 1. We apologize to our colleagues whose work was not cited here owing to space limitations. The work was funded by grants from the Association Francois Aupetit, the IRMAD, the Human Frontier Science Program, the Fondation pour la Recherche Médicale, UCB Pharma and Sanofi-Aventis.

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