A role for membrane-bound CD147 in NOD2-mediated recognition of bacterial cytoinvasion

Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr 12, Kiel, Germany.
Journal of Cell Science (Impact Factor: 5.43). 03/2008; 121(Pt 4):487-95. DOI: 10.1242/jcs.016980
Source: PubMed


NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide. Mutations in the leucine-rich repeat region of NOD2, which lead to an impaired recognition of muramyl dipeptide, have been associated with chronic inflammatory diseases of barrier organs such as Crohn disease, asthma and atopic eczema. In this study we identify CD147 (also known as BSG and EMMPRIN), a membrane-bound regulator of cellular migration, differentiation and inflammatory processes, as a protein interaction partner of NOD2. We demonstrate a complex influence of the CD147-NOD2 interaction on NOD2-dependent signaling responses. We show that CD147 itself acts as an enhancer of the invasion of Listeria monocytogenes, an intracellular bacterial pathogen. We propose that the CD147-NOD2 interaction serves as a molecular guide to regulate NOD2 function at sites of pathogen invasion.

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    • "It has been shown that NOD2 is involved in recognition and defense against various intestinal pathogens, including Helicobacter pylori (43), Helicobacter hepaticus (44), Citrobacter (45), Salmonella typhimurium (46), E. coli (47), and Listeria monocytogenes (40, 48). In CD-affected humans, the link between NOD2 status and intestinal dysbiosis has been confirmed in disease patients homozygous for the NOD2 L1007fsinsC mutation. "
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    ABSTRACT: The host's ability to discriminate friend and foe and to establish a precise homeostasis with its associated microbiota is crucial for its survival and fitness. Among the mediators of intestinal host-microbe interactions, NOD-like receptor (NLR) proteins take center stage. They are present in the epithelial lining and innate immune cells that constantly monitor microbial activities at the intestinal barrier. Dysfunctional NLRs predispose to intestinal inflammation as well as sensitization to extra-intestinal immune-mediated diseases and are linked to the alteration of microbial communities. Here, we review advances in our understanding of their reciprocal relationship in the regulation of intestinal homeostasis and implications for intestinal health.
    Frontiers in Immunology 12/2013; 4:479. DOI:10.3389/fimmu.2013.00479
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    • "The Listeria monocytogenes serotype 1/2a strain EGD was used as a model organism for bacterial infection. Primary human monocytes were infected with Listeria at a multiplicity of infection (MOI) of 100 bacteria/cell as described before [24]. "
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    ABSTRACT: Micro-RNAs (miRNAs) are short, non-coding RNAs that regulate gene expression post transcriptionally. Several studies have demonstrated the relevance of miRNAs for a wide range of cellular mechanisms, however, the current knowledge on how miRNAs respond to relevant external stimuli, e.g. in disease scenarios is very limited. To generate a descriptive picture of the miRNA network associated to inflammatory responses, we quantified the levels of 330 miRNAs upon stimulation with a panel of pro-inflammatory components such as microbial pattern molecules (flagellin, diacylated lipopeptide lipopolysaccharide, muramyl dipeptide), infection with Listeria monocytogenes and TNF-α as pro-inflammatory control in primary human monocytes using real time PCR. As a result, we found distinct miRNA response clusters for each stimulus used. Additionally, we identified potential target genes of three selected miRNAs miR-129-5p, miR-146a and miR-378 which were part of PAMP-specific response clusters by transfecting THP1 monocytes with the corresponding pre- or anti-miRNAs and microfluidic PCR arrays. The miRNAs induced distinct transcriptomal signatures, e.g. overexpression of miRNA129-5p, which was selectively upregulated by the NOD2-elicitor MDP, led to an upregulation of DEFB1, IRAK1, FBXW7 and IKK γ (Nemo). Our findings on highly co-regulated clusters of miRNAs support the hypothesis that miRNAs act in functional groups. This study indicates that miRNAs play an important role in fine-tuning inflammatory mechanisms. Further investigation in the field of miRNA responses will help to understand their effects on gene expression and may close the regulatory gap between mRNA and protein expression in inflammatory diseases.
    PLoS ONE 02/2012; 7(2):e31151. DOI:10.1371/journal.pone.0031151 · 3.23 Impact Factor
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    • "NOD2 regulates the production of inflammatory mediators in response to muramyl dipeptide (MDP) which is found in Gram-negative and Gram-positive bacteria and mycobacteria (Girardin et al., 2003; Coulombe et al., 2009). Many studies have found that NOD2 is able to recognize and generate a response to a variety of microorganisms (Opitz et al., 2004; Ferwerda et al., 2005; Kobayashi et al., 2005; Herskovits et al., 2007; Kapetanovic et al., 2007; Hsu et al., 2008; Kim et al., 2008; Till et al., 2008; Deshmukh et al., 2009; Hruz et al., 2009; Loving et al., 2009). NOD2 senses bacteria through its leucinerich repeats (LRR), then oligomerizes through its NOD domain and is able to recruit receptor interacting protein 2 (RIP2) through an electrostatic interaction of the CARD domain in each protein. "
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    ABSTRACT: Mycobacterium tuberculosis (M.tb), which causes tuberculosis, is a host-adapted intracellular pathogen of macrophages. Intracellular pattern recognition receptors in macrophages such as nucleotide-binding oligomerization domain (NOD) proteins regulate pro-inflammatory cytokine production. NOD2-mediated signalling pathways in response to M.tb have been studied primarily in mouse models and cell lines but not in primary human macrophages. Thus we sought to determine the role of NOD2 in regulating cytokine production and growth of virulent M.tb and attenuated Mycobacterium bovis BCG (BCG) in human macrophages. We examined NOD2 expression during monocyte differentiation and observed a marked increase in NOD2 transcript and protein following 2-3 days in culture. Pre-treatment of human monocyte-derived and alveolar macrophages with the NOD2 ligand muramyl dipeptide enhanced production of TNF-α and IL-1β in response to M.tb and BCG in a RIP2-dependent fashion. The NOD2-mediated cytokine response was significantly reduced following knock-down of NOD2 expression by using small interfering RNA (siRNA) in human macrophages. Finally, NOD2 controlled the growth of both M.tb and BCG in human macrophages, whereas controlling only BCG growth in murine macrophages. Together, our results provide evidence that NOD2 is an important intracellular receptor in regulating the host response to M.tb and BCG infection in human macrophages.
    Cellular Microbiology 10/2010; 13(3):402-18. DOI:10.1111/j.1462-5822.2010.01544.x · 4.92 Impact Factor
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