Trends in Microbiology
OpinionNODs in defence: from vulnerable antimicrobial peptides to chronic inflammation
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.
References (66)
Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
J. Biol. Chem.
(2003)Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease
J. Biol. Chem.
(2003)Nucleotide-binding oligomerization domain-1 and epidermal growth factor receptor: critical regulators of β-defensins during Helicobacter pylori infection
J. Biol. Chem.
(2006)Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis
Cell
(2004)NOD2/CARD15 mediates induction of the antimicrobial peptide human β-defensin-2
J. Biol. Chem.
(2006)β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB
Cell
(2002)Mycobacterium bovis infection of vitamin D-deficient NOS2−/− mice
Microb. Pathog.
(2004)The molecular basis of vitamin D receptor and β-catenin crossregulation
Mol. Cell
(2006)Muramyl dipeptide and Toll-like receptor sensitivity in NOD2-associated Crohn's disease
Lancet
(2005)Crohn's disease and the NOD2 gene: a role for Paneth cells
Gastroenterology
(2003)
A chromosome 8 gene cluster polymorphism with low human β-defensin 2 gene copy number predisposes to Crohn's disease of the colon
Am. J. Hum. Genet.
High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease
Gastroenterology
Antimicrobial therapy to prevent or treat oral mucositis
Lancet Infect. Dis.
Toll-like receptor signaling pathways
Science
NOD-LRR proteins: role in host-microbial interactions and inflammatory disease
Annu. Rev. Biochem.
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Nature
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Nature
Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases
Proc. Natl. Acad. Sci. U. S. A.
Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract
Science
An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid
Nat. Immunol.
Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan
Science
Defensins: antimicrobial peptides of innate immunity
Nat. Rev. Immunol.
Mammalian defensins in the antimicrobial immune response
Nat. Immunol.
Reduced Paneth cell α-defensins in ileal Crohn's disease
Proc. Natl. Acad. Sci. U. S. A.
Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria
Nat. Immunol.
Paneth cell trypsin is the processing enzyme for human defensin-5
Nat. Immunol.
Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense
Science
Characterization of the mouse β-defensin 1, Defb1, mutant mouse model
Infect. Immun.
Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3
Blood
FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis
Proc. Natl. Acad. Sci. U. S. A.
The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection
Nat. Med.
Innate antimicrobial peptide protects the skin from invasive bacterial infection
Nature
Interplay between antibacterial effectors: a macrophage antimicrobial peptide impairs intracellular Salmonella replication
Proc. Natl. Acad. Sci. U. S. A.
Cited by (41)
Interleukin-32 in chronic inflammatory conditions is associated with a higher risk of cardiovascular diseases
2017, AtherosclerosisCitation Excerpt :Accordingly, Netea et al. found that muramyl dipeptide (MDP), a peptidoglycan fragment from bacteria and a potent NOD2 ligand, could induce the expression of IL-32 in a caspase-1-dependent manner. Eventually, this would result in an increased production of IL-6 and IL-1β [20,34]. Interestingly, NOD2 mutations in Crohn's disease (CD) patients were found to cause enhanced IL-1β and NF-κB activity, importantly contributing to disease onset and its activity.
Dysregulation of overexpressed IL-32α in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-κB and Bcl-2
2012, Cancer LettersCitation Excerpt :Netea et al. demonstrated that IL-32 augments the production of IL-1β and IL-6 induced by muramyl dipeptide (MDP), a peptidoglycan fraction of bacteria, by means of the nucleotide-binding oligomerization domain proteins (NOD1 and NOD2) through a caspase-1-dependent mechanisms [5]. NODs are family of intracytoplasmic bacterial sensors, and recognition of bacterial peptidoglycans subsequently induces NF-κB activation [7]. Mutations in NOD2 have been implicated in the pathogenesis of Crohn’s disease (CD) [8,9], and CD patients homozygous for frameshift 3020insC mutated allele have defective responses to MDP in cytokine production [10–12].
Lessons from the inflammasome: a molecular sentry linking Candida and Crohn's disease
2010, Trends in ImmunologyCitation Excerpt :Additionally, translocating mannan might subsequently precipitate granuloma formation at sites of intestinal breaches in CD patients by inhibiting the antimicrobial activity of macrophages [40]. So, it is more likely that a primary antimicrobial peptide deficiency will result in poor control of microbial colonisation and therefore enhanced mucosal inflammation at intestinal sections with high microbial content [37]. Besides the main contribution of NOD2 variants in the genetic propensity of CD [41], recent genome-wide association studies have revealed that frequent variants of NLRP3 and an NLRP3-coupling adaptor, referred to as CARD8 or CARDINAL, predispose hosts to CD development (Figure 1) [42,43].
NOD Receptor Recognition of Peptidoglycan
2010, Microbial GlycobiologyNOD receptor recognition of peptidoglycan
2009, Microbial Glycobiology: Structures, Relevance and ApplicationsOral and gut dysbiosis leads to functional alterations in Parkinson’s disease
2022, npj Parkinson's Disease