Gene–environment interaction modulated by allelic heterogeneity in inflammatory diseases

Chamaillard, Mathias; Philpott, Dana J.; Girardin, Stephen E.; Zouali, Habib; Lesage, Suzanne; Chareyre, Fabrice; Bui, The Hung; Giovannini, Marco; Zaehringer, Ulrich; Penard-Lacronique, Virginie; Sansonetti, Philippe J.; Hugot, Jean‐Pierre; Thomas, Gilles

doi:10.1073/pnas.0530276100

Cited by 283 publications

(237 citation statements)

References 35 publications

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“…Consistent with our functional data, I352S is the only polymorphism among all identified in the NACHT domain of NLRP2 that localizes in a position aligned with a disease-associated variation (E441K in NOD2) in either NLRP3 or NOD2 proteins. It has been shown that the E441K change has an impact on the NOD2-mediated activation of NF-B in response to bacterial peptidoglycan and is considered a rare polymorphism associated with Crohn's disease (38). Taking into account the complex control on the activation of NF-B and the increasing number of proteins involved, analyses of deleterious or activating polymorphisms in candidate genes will be needed to decipher their contribution to chronic inflammatory disorders or autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

NLRP2, an Inhibitor of the NF-κB Pathway, Is Transcriptionally Activated by NF-κB and Exhibits a Nonfunctional Allelic Variant

Fontalba

Gutiérrez

Fernández-Luna

2007

The Journal of Immunology

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NLRP2 has been shown to inhibit the NF-κB signaling pathway, and thus may contribute to modulate the inflammatory response, where NF-κB plays a major role. In this study, we report that expression of NLRP2 is induced upon differentiation of CD34+ hemopoietic progenitors into granulocyte or monocyte/macrophages. We also found that NLRP2 was up-regulated following differentiation of mesenchymal stem cells toward adipocytes. Notably, stimulation of HEK293T cells with TNF-α or overexpression of the p65 subunit of NF-κB resulted in up-regulation of NLRP2 and the formation of NF-κB-NLRP2 promoter complexes. Moreover, ectopic expression of p65 but not of other transcriptional regulators induced transactivation of the NLRP2 promoter. Thus, NLRP2 may control NF-κB activation through a regulatory loop. Nucleotide changes within the NACHT domain of other NLRP proteins have been associated with hereditary fever syndromes and chronic inflammatory diseases. We identified five single nucleotide polymorphisms present in the NACHT domain of NLRP2 by sequencing genomic DNA from 319 healthy controls. The frequencies of the rare alleles varied between 0.2 and 10%. Of note, one of these variants, I352S was unable to block the transcriptional activity of NF-κB and the formation of NF-κB-DNA-binding complexes following stimulation with TNF-α. Overall, our findings provide molecular insight into the expression of NLRP2 by NF-κB and suggest that a polymorphism within the NACHT domain of NLRP2 may contribute to the amplification of inflammatory responses due to a reduction of inhibitory signals on the NF-κB pathway.

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Section: Discussionmentioning

confidence: 99%

NLRP2, an Inhibitor of the NF-κB Pathway, Is Transcriptionally Activated by NF-κB and Exhibits a Nonfunctional Allelic Variant

Fontalba

Gutiérrez

Fernández-Luna

2007

The Journal of Immunology

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“…51 Nod1, in contrast, has a narrow specificity and recognizes only DAP-type PG, which constitutes a signature of most Gram-negative bacterial PGs. 43 Nod1 detects efficiently the naturally occurring muropeptide GM-L-Ala-DGlu-mesoDAP, but the minimal motif found to activate human Nod1 is the dipeptide D-Glu-mesoDAP.…”

Section: Nods and Pg Motifsmentioning

confidence: 99%

“…63 Recurrent mutations in the central NACHT domain from NOD2 have been linked with these diseases. 109 Compared to wild-type NOD2, the most frequently found mutation, R334Q, leads to increased basal NF-kB activation, in the absence of ligand, 51 and further increased NF-kB activation upon MDP stimulation. 55 Noticeably, Crohn's disease and BS are both characterized by a granulomatosis disorder, but mutations in NOD2 associated with these diseases have opposite effects on the NF-kB activation.…”

Section: Nod2mentioning

confidence: 99%

TIR, CARD and PYRIN: three domains for an antimicrobial triad

2006

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Innate immunity to microorganisms in mammals has gained a substantial interest during the last decade. The discovery of the Toll-like receptor (TLR) family has allowed the identification of a class of membrane-spanning receptors dedicated to microbial sensing. TLRs transduce downstream signaling via their intracellular Toll-interleukin-1 receptor (TIR) domain. More recently, the role of intracellular microbial sensors has been uncovered. These molecules include the Nod-like receptors Nod1, Nod2, Ipaf and Nalps, together with the helicase domain-containing antiviral proteins RIG-I and Mda-5. The intracellular microbial sensors lack the TIR domain, but instead transduce downstream signals via two domains also implicated in homophilic protein-protein interactions, the caspase activation and recruitment domain (CARD) and PYRIN domains. In light with these recent findings, we propose that TIR, CARD and PYRIN domains represent the three arms of innate immune detection of microorganisms in mammals.

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“…These studies suggested that RICK is involved in TLR signaling. However, many preparations of bacterial components contain Nod1-and Nod2-stimulating molecules (4,5,7,15,16) and the presence of such contaminants could also explain reduced TLR signaling in RICK-deficient macrophages. In the present report, we have studied the role of RICK in TLR signaling in macrophages and in the animal.…”

mentioning

confidence: 99%

RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs

Park

Kim

McDonald

et al. 2007

The Journal of Immunology

463

422

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RICK is a kinase that has been implicated in Nod1 and Nod2 signaling. In addition, RICK has been proposed to mediate TLR signaling in that its absence confers reduced responses to certain bacterial products such as LPS. We show here that macrophages and mice lacking RICK are defective in their responses to Nod1 and Nod2 agonists but exhibit unimpaired responses to synthetic and highly purified TLR agonists. Furthermore, production of chemokines induced by the bacterial dipeptide γ-d-glutamyl-meso-diaminopimelic acid was intact in MyD88 deficient mice but abolished in RICK-null mice. Stimulation of macrophages with muramyl dipeptide, the Nod2 activator, enhanced immune responses induced by LPS, IFN-γ, and heat-killed Listeria in wild-type but not in RICK- or Nod2-deficient macrophages. Finally, we show that the absence of RICK or double deficiency of Nod1 and Nod2 was associated with reduced cytokine production in Listeria-infected macrophages. These results demonstrate that RICK functions in innate immunity by mediating Nod1 and Nod2 signaling but not TLR-mediated immune responses.

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Gene–environment interaction modulated by allelic heterogeneity in inflammatory diseases

Cited by 283 publications

References 35 publications

NLRP2, an Inhibitor of the NF-κB Pathway, Is Transcriptionally Activated by NF-κB and Exhibits a Nonfunctional Allelic Variant

NLRP2, an Inhibitor of the NF-κB Pathway, Is Transcriptionally Activated by NF-κB and Exhibits a Nonfunctional Allelic Variant

TIR, CARD and PYRIN: three domains for an antimicrobial triad

RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs

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