NOD-Like Receptors: Guardians of Intestinal Mucosal Barriers

Claes, Anne-Kathrin; Zhou, Jun; Philpott, Dana J.

doi:10.1152/physiol.00025.2014

Cited by 52 publications

(41 citation statements)

References 120 publications

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“…Gut microbes impact local and systemic inflammation through pattern recognition receptors (PRRs) [147, 148]. Accumulating evidence has revealed that gut microbes may regulate fat mass expansion via their fermentative products and mediate the suppression of the fasting induced adipose factor [69, 149–152].…”

Section: Reviewmentioning

confidence: 99%

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases

2017

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BackgroundA vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health.MethodsThis paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA).ResultsIn addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction.ConclusionsA better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.

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Section: Reviewmentioning

confidence: 99%

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases

2017

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“…Pattern recognition receptors (PRRs) are innate immune components, which mainly involves Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs). PRRs are expressed in intestinal epithelial cells [11,12] and are able to recognize microbial-associated molecular patterns (MAMPs) to develop either inflammatory or tolerance responses [13]. In this context, several studies have reported that numerous PRRs, as TLR2, TLR4 [14] and NOD2 [15], seem to be implicated in IBD due to the dysfunctional recognition of commensal microbiota [16].…”

Section: Introductionmentioning

confidence: 99%

“…NOD2 plays a key role in intestinal homeostasis, developing a tolerance response to the commensal microbiota and protecting the host against pathogenic microorganisms through pro-inflammatory intracellular pathways, such as NF-κB [11].…”

Section: Introductionmentioning

confidence: 99%

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Layunta

Latorre

Forcén

et al. 2018

Cell Physiol Biochem

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Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression.

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“…TLRs and NLRs recognize common motifs present in bacteria and viruses with some specificities and complementarities allowing the detection, sampling and coordinated response to microbiological insults. NOD2 belongs to the NLR family and this protein is essential to control inflammation of the intestinal mucosa in permanent contact with commensal bacteria [1, 2]. After binding to its peptidoglycan derived MDP ligand, NOD2 and RICK will interact strongly leading to TAK1 recruitment.…”

Section: Introductionmentioning

confidence: 99%

Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins

et al. 2016

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NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, inducing gene transcription and synthesis of proteins required to initiate a balanced immune response. Mutations in NOD2 have been associated with an increased risk of Crohn’s Disease (CD), a disabling inflammatory bowel disease (IBD). Because NOD2 signaling plays a key role in CD, it is important to further characterize the network of protein interacting with NOD2. Using yeast two hybrid (Y2H) screens, we identified new NOD2 interacting proteins (NIP). The primary interaction was confirmed by coimmunoprecipitation and/or bioluminescence resonance energy transfer (BRET) experiments for 11 of these proteins (ANKHD1, CHMP5, SDCCAG3, TRIM41, LDOC1, PPP1R12C, DOCK7, VIM, KRT15, PPP2R3B, and C10Orf67). These proteins are involved in diverse functions, including endosomal sorting complexes required for transport (ESCRT), cytoskeletal architecture and signaling regulation. Additionally, we show that the interaction of 8 NIPs is compromised with the 3 main CD associated NOD2 mutants (R702W, G908R and 1007fs). Furthermore, to determine whether these NOD2 protein partners could be encoded by IBD susceptibility genes, a transmission disequilibrium test (TDT) was performed on 101 single nucleotide polymorphisms (SNPs) and the main corresponding haplotypes in genes coding for 15 NIPs using a set of 343 IBD families with 556 patients. Overall this work did not increase the number of IBD susceptibility genes but extends the NOD2 protein interaction network and suggests that NOD2 interactome and signaling depend upon the NOD2 mutation profile in CD.

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NOD-Like Receptors: Guardians of Intestinal Mucosal Barriers

Cited by 52 publications

References 120 publications

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins

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