Impaired dendritic cell function in Crohn’s disease patients with NOD2 3020insC mutation

Kramer, Matthijs; Netea, Mihai G.; Jong, Dirk J. de; Kullberg, Bart Jan; Adema, Gosse J.

doi:10.1189/jlb.0805484

Cited by 87 publications

(65 citation statements)

References 32 publications

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“…However, a recent study utilizing mice with the same gene knocked in demonstrated a lossof-function phenotype with reduced levels of cytokine in response to MDP and bacterial infection (61). These later findings concur with studies utilizing cells from CD patients, suggesting a loss-offunction mutation (15,16,(62)(63)(64)(65). When the response of cells from CD patients bearing NOD2 mutations was compared with cells with WT NOD2, the potentiation of cytokine response by MDP was lost in patients with mutated NOD2 (14)(15)(16).…”

Section: Discussionsupporting

confidence: 52%

Nucleotide-Binding Oligomerization Domain 2 Signaling Promotes Hyperresponsive Macrophages and Colitis in IL-10–Deficient Mice

Jamontt¹,

Petit

Clark

et al. 2013

The Journal of Immunology

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IL-10 contributes to the maintenance of intestinal homeostasis via the regulation of inflammatory responses to enteric bacteria. Loss of IL-10 signaling results in spontaneous colitis in mice and early onset enterocolitis in humans. Nucleotide-binding oligomerization domain (NOD) 2 is an intracellular receptor of bacterial peptidoglycan products, and, although NOD2 mutations are associated with Crohn’s disease, the precise role of NOD2 in the development of intestinal inflammation remains undefined. To determine the role of NOD2 in the development of colitis on the clinically relevant genetic background of IL-10–deficient signaling, we generated mice lacking IL-10 and NOD2 (IL-10−/−NOD2−/−). Loss of NOD2 in IL-10−/− mice resulted in significant amelioration of chronic colitis, indicating that NOD2 signaling promotes the development of intestinal inflammation in IL-10−/− mice. Contrary to previous reports investigating immune function in NOD2−/− mice, T cell proliferative capacity and IL-2 production were not impaired, and immune polarization toward type 1 immunity was not affected. However, loss of NOD2 in IL-10–deficient macrophages reduced IL-6, TNF-α, and IL-12p40 production in response to bacterial stimulation. Further analysis of the intrinsic macrophage response before the onset of inflammation revealed that, in the absence of IL-10, synergistic signaling between various TLRs and NOD2 resulted in hyperresponsive, proinflammatory macrophages, thus providing the appropriate immune environment for the development of colitis. Data presented in this study demonstrate that NOD2 signaling contributes to intestinal inflammation that arises through loss of IL-10 and provides mechanistic insight into the development of colitis in inflammatory bowel disease patients with impaired IL-10 signaling.

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Section: Discussionsupporting

confidence: 52%

Nucleotide-Binding Oligomerization Domain 2 Signaling Promotes Hyperresponsive Macrophages and Colitis in IL-10–Deficient Mice

Jamontt¹,

Petit

Clark

et al. 2013

The Journal of Immunology

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“…Each of the three CD polymorphisms are located within or near the leucine rich repeat, sensing domain of Nod2, and each results in a decreased capacity to activate NF-κB in response peptidoglycan or MDP stimulation [39,[44][45][46][47][48] . The frameshift mutation, Leu1007fsinsC demonstrates a largely complete deficiency in the capacity to signal in response to MDP stimulation [45] .…”

Section: Nod2 (Card15) Associations To Ileal CDmentioning

confidence: 99%

“…As each of the three major mutations demonstrates decreased function in primary human cells [39,[44][45][46][47][48] , Nod2-deficient murine models provide an important model for human disease. The absence of intestinal inflammation in Nod2-deficient mice further highlights the insufficiency of this pathway alone to induce CD [42,53] .…”

Section: Nod2 (Card15) Associations To Ileal CDmentioning

confidence: 99%

Inflammatory bowel disease: Genetic and epidemiologic considerations

Cho

2008

WJG

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Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn's disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.

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“…The second model involves altered TLR2 signaling, proposing an inhibitory role of Nod2 in the TLR2-mediated Th1 responses (17). However, other groups have shown that TLR2 responses are normal in different lines of Nod2-deficient mice, and there may be a synergistic rather than a negative effect on TLR2 stimulation in human and mouse cells (10,(18)(19)(20)(21). The third model proposes that mutations in NOD2 may result in altered mucosal host-microbe interactions (13).…”

mentioning

confidence: 99%

Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum

Biswas

Liu

Hao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

149

140

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Mutations in the NOD2 gene are strong genetic risk factors for ileal Crohn’s disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject of controversy. We report that Nod2 -deficient mice inoculated with Helicobacter hepaticus , an opportunistic pathogenic bacterium, developed granulomatous inflammation of the ileum, characterized by an increased expression of Th1-related genes and inflammatory cytokines. The Peyer’s patches and mesenteric lymph nodes were markedly enlarged with expansion of IFN-γ–producing CD4 and CD8 T cells. Rip2 -deficient mice exhibited a similar phenotype, suggesting that Nod2 function likely depends on the Rip2 kinase in this model. Transferring wild-type bone marrow cells into irradiated Nod2 -deficient mice did not rescue the phenotype. However, restoring crypt antimicrobial function of Nod2 -deficient mice by transgenic expression of α-defensin in Paneth cells rescued the Th1 inflammatory phenotype. Therefore, through the regulation of intestinal microbes, Nod2 function in nonhematopoietic cells of the small intestinal crypts is critical for protecting mice from a Th1-driven granulomatous inflammation in the ileum. The model may provide insight into Nod2 function relevant to inflammation of ileal Crohn’s disease.

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Impaired dendritic cell function in Crohn’s disease patients with NOD2 3020insC mutation

Cited by 87 publications

References 32 publications

Nucleotide-Binding Oligomerization Domain 2 Signaling Promotes Hyperresponsive Macrophages and Colitis in IL-10–Deficient Mice

Nucleotide-Binding Oligomerization Domain 2 Signaling Promotes Hyperresponsive Macrophages and Colitis in IL-10–Deficient Mice

Inflammatory bowel disease: Genetic and epidemiologic considerations

Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum

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