MDP and other muropeptides – direct and synergistic effects on the immune system

Traub, Stephanie; Aulock, Sonja von; Hartung, Thomas; Hermann, Corinna

doi:10.1179/096805106x89044

Cited by 81 publications

(58 citation statements)

References 174 publications

(152 reference statements)

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“…muramyl dipeptide is released via digestion of PGN by host lytic enzymes, such as lysozyme and amidase [31]. It is transported by the transporter protein PepT1 into the intestinal epithelium, where it comes into contact with NOD2 [32].…”

Section: Discussionmentioning

confidence: 99%

Butyrate mediates nucleotide‐binding and oligomerisation domain (NOD) 2‐dependent mucosal immune responses against peptidoglycan

Leung

Lam

et al. 2009

Eur J Immunol

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The interaction between digestive tract microbiological flora and food has an important influence on human health. Butyrate is produced during the fermentation of dietary fibres by intestinal bacteria and plays an important role in the regulation of mucosal immunity. In this report, we studied the impact of butyrate on the defence mechanism against the bacterial membrane component peptidoglycan (PGN). Butyrate was found to enhance PGN-mediated IL-8 and GRO-a production. The expression of these chemokines required the activation of NF-jB and was dependent on the concentrations of butyrate and PGN. Butyrate was found to up-regulate nucleotide-binding and oligomerisation domain (NOD) 2, but not NOD1 or TLR2. NOD2 up-regulation was mediated by an increase in histone acetylation in the Nod2 promoter region, leading to enhanced PGN-induced IL-8 and GRO-a secretion. Knockdown of NOD2 and TLR2 by siRNA significantly reduced PGNmediated chemokine production, suggesting that both NOD2 and TLR2 are required for maximal response. Our findings provide a better understanding of the mechanism by which butyrate regulates mucosal immunity for normal intestinal function. Based on the results of this study, we infer that dietary fibres can impact inflammatory bowel diseases.Key words: Butyrate . Intestinal immunity . Nucleotide-binding and oligomerization domains (NOD) .Peptidoglycan . TLR IntroductionIntestinal epithelial cells (IEC) function as a physical barrier against foreign substances in the intestinal lumen, such as food and pathogenic and non-pathogenic microorganisms. These cells are also involved in the host immune defence. Cytokines or chemokines are produced by IEC in response to potentially harmful substances, which are detected by a battery of pathogenrecognition receptors. These receptors are involved in the regulation of physiological and pathophysiological processes of the intestinal mucosa, including immunity and inflammation, via activation of MAPK and the key transcription factor, NF-kB [1][2][3][4]. The first widely studied family of receptors was the TLR family. Eleven mammalian TLR have been identified, of which TLR1-6 and TLR9 are expressed in IEC [3][4][5]. Another group of pathogenrecognition receptors, termed nucleotide-binding and oligomerisation domain (NOD) proteins, provide a second line of innate immune defence against bacterial infection. This family consists of more than 20 members and is located primarily in the cytosol. While NOD1 is constitutively expressed in IEC, the level of NOD2 expression is very low [1,2]. The bi-directional interaction between digestive tract microbiological flora and food has an important influence on human health, particularly on the immune response [6,7]. Butyrate is There is an increasing body of evidence demonstrating the importance of butyrate in maintaining intestinal mucosal immunity [9][10][11]. Butyrate has been shown to switch the transcriptional pattern of chemokine production through promotion of histone acetylation [12]. Several studies have also suggested...

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Section: Discussionmentioning

confidence: 99%

Butyrate mediates nucleotide‐binding and oligomerisation domain (NOD) 2‐dependent mucosal immune responses against peptidoglycan

Leung

Lam

et al. 2009

Eur J Immunol

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“…These studies suggest that only the active Nod2 ligand, MDP, can induce bacteria killing of both Gram-positive and Gram-negative bacteria. Although MDP is not a Toll-like receptor (TLR) ligand, there is crosstalk between TLR and Nod2 signaling (2,10,15). However, MDP-induced secretion is not mediated by TLRs, because the active Nod2 ligand, MDP, and CCH, but not the inactive chiral isomer of MDP, could induce bacteria-killing activity in MyD88-deficient crypts (Fig.…”

Section: The Nod2 Ligand Induces Bacteria-killing Activity In Intestimentioning

confidence: 99%

“…1A) (25). It is known that chirality in the peptide chain of MDP is critical for Nod2 activation: MDP can activate Nod2, whereas chiral isomers such as N-acetylmuramyl-D-alanyl-D-isoglutamine (MDP DD ) and Nacetylmuramyl-L-alanyl-L-isoglutamine (MDP LL ) cannot (10). To assess the specificity of MDP for the induction of bacteria killing in this assay, we used inactive MDP chiral isomers.…”

Section: The Nod2 Ligand Induces Bacteria-killing Activity In Intestimentioning

confidence: 99%

“…Nod2 has been shown to respond to muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), a moiety of peptidoglycan consisting of N-acetylmuramyl-L-Ala-D-Glu (8,9). This moiety is conserved in both Gram-positive and Gram-negative peptidoglycan, suggesting that Nod2 may detect a wide variety of bacteria (10). The Rip2 kinase is required for downstream signaling of Nod2 (11).…”

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confidence: 99%

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Nod2 is required for the regulation of commensal microbiota in the intestine

Petnicki‐Ocwieja

Hrncírová

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

508

450

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Mutations in the Nod2 gene are among the strongest genetic risk factors in the pathogenesis of ileal Crohn's disease, but the exact contributions of Nod2 to intestinal mucosal homeostasis are not understood. Here we show that Nod2 plays an essential role in controlling commensal bacterial flora in the intestine. Analysis of intestinal bacteria from the terminal ilea of Nod2-deficient mice showed that they harbor an increased load of commensal resident bacteria. Furthermore, Nod2-deficient mice had a diminished ability to prevent intestinal colonization of pathogenic bacteria. In vitro, intestinal crypts isolated from terminal ilea of Nod2-deficient mice were unable to kill bacteria effectively, suggesting an important role of Nod2 signaling in crypt function. Interestingly, the expression of Nod2 is dependent on the presence of commensal bacteria, because mice re-derived into germ-free conditions expressed significantly less Nod2 in their terminal ilea, and complementation of commensal bacteria into germ-free mice induced Nod2 expression. Therefore, Nod2 and intestinal commensal bacterial flora maintain a balance by regulating each other through a feedback mechanism. Dysfunction of Nod2 results in a break-down of this homeostasis.commensal bacteria ͉ Crohn's disease ͉ mouse ͉ NLR

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“…These glycan chains are composed of alternating Nacetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) with the amino acids coupled to the muramic acid. Muropeptides are breakdown products of PGN that bear at least the MurNAc moity and one amino acid (Traub et al, 2006). One of the prominent muropeptides is muramyl dipeptide (MDP), which is known since the 1970s.…”

Section: Muramyl Dipeptide and Other Muropeptidesmentioning

confidence: 99%