Article

Fritz JH, Ferrero RL, Philpott DJ, Girardin SE.. Nod-like proteins in immunity, inflammation and disease. Nat Immunol 7: 1250-1257

Department of Immunology, Medical Sciences Building, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Nature Immunology (Impact Factor: 20). 01/2007; 7(12):1250-7. DOI: 10.1038/ni1412
Source: PubMed

ABSTRACT

The intracellular Nod-like proteins or receptors are a family of sensors of intracellularly encountered microbial motifs and 'danger signals' that have emerged as being critical components of the innate immune responses and of inflammation in mammals. Several Nod-like receptors, including Nod1, Nod2, NALP3, Ipaf and Naip, are strongly associated with host responses to intracellular invasion by bacteria or the intracellular presence of specific bacterial products. An additional key function of Nod-like receptors is in inflammatory conditions, which has been emphasized by the identification of several different mutations in the genes encoding Nod1, Nod2 and NALP3 that are associated with susceptibility to inflammatory disorders. Those and other issues related to the Nod-like receptor family are discussed here.

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Available from: Jorg Hermann Fritz, Jul 15, 2014
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    • "Cells of the middle ear mucosa (MEM) express various pattern recognition receptors (PRRs) that interact with pathogens or pathogen associated molecular patterns (PAMPs) regulating the expression of inflammatory cytokines, interferons, and antimicrobial peptides [2]. Some PRRs are also involved in the regulation of apoptosis and mediate innate resistance mechanisms against intracellular microbes [3] [4] [5]. A very important family of PRRs is the Toll-like receptors (TLRs) [2]. "
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    ABSTRACT: Background: Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis or intracranial complications. The etiopathogenesis of cholesteatoma is controversial, but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors and their associated signaling networks was investigated in cholesteatoma, since mutations in NOD-like receptor-related genes have been implicated in other chronic inflammatory disorders. Results: The expression of NOD2 mRNA and protein were significantly induced in cholesteatoma compared to the external auditory canal skin, mainly located in the epithelial layer of cholesteatoma. Microarray analysis showed significant upregulation for NOD2, not for NOD1, TLR2 or TLR4 in cholesteatoma. Moreover, regulation of 44 genes in an interaction network of the NOD-adaptor molecule RIPK2 was detected. In addition to NOD2, NLRC4, PYCARD, the downstream molecules IRAK1 and anti-46 apoptotic regulator CFLAR, showed significant upregulation, whereas SMAD3, a pro-47 apoptotic inducer, was significantly downregulated. Finally, altered regulation of 48 inflammatory target genes of NOD signaling was detected. Conclusions: These results indicate that the interaction of innate immune signaling mediated by NLRs and their downstream target molecules are involved in the etiopathogenesis and growth of cholesteatoma.
    Full-text · Article · Mar 2015 · BioMed Research International
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    • "Cells of the middle ear mucosa (MEM) express various pattern recognition receptors (PRRs) that interact with pathogens or pathogen associated molecular patterns (PAMPs) regulating the expression of inflammatory cytokines, interferons, and antimicrobial peptides [2]. Some PRRs are also involved in the regulation of apoptosis and mediate innate resistance mechanisms against intracellular microbes [3] [4] [5]. A very important family of PRRs is the Toll-like receptors (TLRs) [2]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis, or intracranial complications. The etiopathogenesis of cholesteatoma is controversial but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors, and their associated signaling networks was investigated in cholesteatoma, since mutations in NOD-like receptor-related genes have been implicated in other chronic inflammatory disorders. Results. The expression of NOD2 mRNA and protein was significantly induced in cholesteatoma compared to the external auditory canal skin, mainly located in the epithelial layer of cholesteatoma. Microarray analysis showed significant upregulation for NOD2, not for NOD1, TLR2, or TLR4 in cholesteatoma. Moreover, regulation of genes in an interaction network of the NOD-adaptor molecule RIPK2 was detected. In addition to NOD2, NLRC4, and PYCARD, the downstream molecules IRAK1 and antiapoptotic regulator CFLAR showed significant upregulation, whereas SMAD3, a proapoptotic inducer, was significantly downregulated. Finally, altered regulation of inflammatory target genes of NOD signaling was detected. Conclusions. These results indicate that the interaction of innate immune signaling mediated by NLRs and their downstream target molecules is involved in the etiopathogenesis and growth of cholesteatoma.
    Full-text · Article · Mar 2015 · BioMed Research International
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    • "In mammals, most NACHT-family members contain three distinct functional domains: an amino-terminal effector-binding domain (EBD), a central NACHT domain and a carboxy-terminal ligand-recognition domain (LRD) (Inohara & Nuñez, 2003). The EBD is structurally variable, with four EBDs, including CARD, PYD, BIR and AD (activation domain) domain present in NACHT-family (Inohara & Nuñez, 2003; Fritz et al., 2006). LRD in most NACHT-family members is leucine-rich repeats (LRRs), except that in human NOD8 the LRD lacks (Inohara & Nuñez, 2003). "
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    ABSTRACT: Lower vertebrates have been found to possess over 200 NACHT-domain encoding genes; but, to date, very little is known about their functional activity. This article describes the sequences and expression analysis of two zebrafish NACHT-containing proteins, namely NALPL1 and NALPL2. In addition, the functions of zebrafish NALPL1 and NALPL2, which are absent for both amino-terminal effector-binding domain (EBD) and carboxy-terminal ligand-recognition domain (LRD), were investigated for the first time in fish species. The predicted NALPL1 and NALPL2 proteins consist of 651 and 847 amino acids (aa), respectively, with both molecules only containing NACHT domain, which were different from other NACHT-family members. Phylogenetic analysis showed that zebrafish NALPL1 and NALPL2 have a closer relationship with mammalian NALP subfamily than NOD subfamily. The differential expression patterns of NALPL1 and NALPL2 in development stages and organs were observed, suggesting the difference of action phase and effector organ of NALPL1 and NALPL2. When the modulation of NALPL1 and NALPL2 in pathogen infection was analyzed, it was found that the two molecules were upregulated by both bacterial and viral infection. Overexpression of NALPL1 and NALPL2 resulted in significant inhibition for intracellular Edwardsiella tarda growth. Further studies demonstrated that NALPL1 and NALPL2 also contributed to protection against viral infection. These results demonstrate that both NALPL1 and NALPL2 are important intracellular proteins in host surveillance against both bacterial and viral infection. Interestingly, the expression of downstream signaling genes was not affected by the overexpression of NALPL1 or NALPL2, but NOD1 and MDA5 were upregulated by NALPL1 or NALPL2 overexpression, suggesting that they likely act in pathogen infection through the interaction with other PRRs.
    Full-text · Article · Oct 2014 · Developmental & Comparative Immunology
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