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Review
. 2013 Sep;70(18):3391-404.
doi: 10.1007/s00018-012-1246-4. Epub 2012 Dec 29.

Muramyl dipeptide responsive pathways in Crohn's disease: from NOD2 and beyond

Mohammad Salem  1 , Jakob Benedict Seidelin, Gerhard Rogler, Ole Haagen Nielsen
Affiliations
Review

Muramyl dipeptide responsive pathways in Crohn's disease: from NOD2 and beyond

Mohammad Salem et al. Cell Mol Life Sci. 2013 Sep.

Abstract

Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including-but not restricted to-nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.

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Figures

Fig. 1
Fig. 1
Mechanisms of MDP intracellular delivery. a Extracellular MDP can permeabilize the host cell through membrane receptors such as hPepT1 and Pennexin-1. b Extracellular MDP can also be transported into the host cell by clathrin- and dynamin-dependent endocytic pathways. c Moreover, MDP can be derived from bacteria by the intracellular phagocytic cleavage. d Finally, MDP can additionally be released to the cytosol through autolysis of internalized of invasive bacteria
Fig. 2
Fig. 2
Structure of NOD2. The structure of NOD2 consists of two N-terminal caspase recruitment domains (CARDs) which mediate protein–protein interactions, a centrally located nucleotide-binding domain (NBD) which mediates protein self-oligomerization required for activation, and C-terminal of site of ligand binding, i.e. leucine-rich repeats (LRRs)
Fig. 3
Fig. 3
Signaling pathway of NOD2. Recognition of MDP through LRRs domain activates NOD2 and causes a conformational change, allowing a CARD–CARD interaction between NOD2 and RIP2, receptor-interacting protein 2 (also known as caspase like regulatory protein (CLARP) kinase). Activation of RIP2 upon binding with NOD2 results in activation of MAPK and NF-κB signaling pathways. RIP2 induces polyubiquitination (ub) of NEMO, NF-κB essential modifier (or IKKγ, inhibitor of IκB kinase γ), which is found in complex with IKKα and IKKβ. This is followed by the phosphorylation of IKKβ as well as the phosphorylation of IκB, inhibitor of NF-κB, and the release of NF-κB. NF-κB can subsequently translocate into the nucleus and promote transcription of many pro-inflammatory and anti-inflammatory cytokines, including interleukin-1 (IL-1), IL-2, IL-6, IL-8, IL-12, and TNF-α
Fig. 4
Fig. 4
MDP activation of pro-inflammatory cytokines through inflammasome-mediated pathway. The prototype structures of NLRP1, NLRP3 and NLRC4 consist of the following major interaction domains: The ligand sensing leucine-rich repeats (LRR), NACHT or the oligomerization domain, pyrin domain (PYD), or caspase recruitment domain (CARD), and function to find domain (FIIND). MDP interaction with these NLRs leads to the formation of inflammasomes, which are able to convert pro-inflammatory cytokines into their biologically active form
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