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A novel crosstalk between TLR4- and NOD2-mediated signaling in the regulation of intestinal inflammation.

Kim H, Zhao Q, Zheng H, Li X, Zhang T, Ma X - Sci Rep (2015)

Bottom Line: Specifically, NOD2 is able to sense the intensity of TLR4-mediated signaling, resulting in either synergistic stimulation of Interluekin-12 (IL-12) production when the TLR signaling intensity is low; or in the inhibition of IL-12 synthesis and maintenance of intestinal mucosal homeostasis when the TLR signaling intensifies.Additionally, in contrast to the dogma, we find that the major Crohn's disease-associated NOD2 mutations could cause a primarily immunodeficient phenotype by selectively impairing TLR4-mediated IL-12 production and host defense.To restore the impaired homeostasis would be a way forward to developing novel therapeutic strategies for inflammatory bowel diseases.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology and School of Life Sciences &Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China 200240.

ABSTRACT
Although Toll-like receptor 4 (TLR4)- and nucleotide-binding oligomerization domain 2 (NOD2)-mediated signaling mechanisms have been extensively studied individually, the crosstalk between them in the regulation of intestinal mucosal defense and tissue homeostasis has been underappreciated. Here, we uncover some novel activities of NOD2 by gene expression profiling revealing the global nature of the cross-regulation between TLR4- and NOD2-mediated signaling. Specifically, NOD2 is able to sense the intensity of TLR4-mediated signaling, resulting in either synergistic stimulation of Interluekin-12 (IL-12) production when the TLR signaling intensity is low; or in the inhibition of IL-12 synthesis and maintenance of intestinal mucosal homeostasis when the TLR signaling intensifies. This balancing act is mediated through receptor-interacting serine/threonine kinase 2, and the transcriptional regulator CCAAT/enhancer-binding protein α (C/EBPα) via its serine 248 phosphorylation by Protein Kinase C. Mice deficient in C/EBPα in the hematopoietic compartment are highly susceptible to chemically induced experimental colitis in an IL-12-dependent manner. Additionally, in contrast to the dogma, we find that the major Crohn's disease-associated NOD2 mutations could cause a primarily immunodeficient phenotype by selectively impairing TLR4-mediated IL-12 production and host defense. To restore the impaired homeostasis would be a way forward to developing novel therapeutic strategies for inflammatory bowel diseases.

No MeSH data available.


Related in: MedlinePlus

Clustering analysis of RNAseq profiling in WT vs NOD2 KO macrophages.RNA samples from WT and NOD2 KO macrophages treated with MDP or LPS or both were subjected to NexGen RNA-sequencing (whole exon). Genes of low expressions (RPKM <0.0) were filtered out. The RPKM values were further normalized per gene over all samples, to be specific, for each gene the mean and standard deviation (stddev) of RPKM over all samples were calculated, and the RPKM was linearly transformed using the formula (rpkm-mean)/stddev. The heatmap was then generated by heatmap.2 in the R gplots package. By default, heatmap.2 uses Euclidean measure to obtain distance matrix and complete agglomeration method for clustering.
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f2: Clustering analysis of RNAseq profiling in WT vs NOD2 KO macrophages.RNA samples from WT and NOD2 KO macrophages treated with MDP or LPS or both were subjected to NexGen RNA-sequencing (whole exon). Genes of low expressions (RPKM <0.0) were filtered out. The RPKM values were further normalized per gene over all samples, to be specific, for each gene the mean and standard deviation (stddev) of RPKM over all samples were calculated, and the RPKM was linearly transformed using the formula (rpkm-mean)/stddev. The heatmap was then generated by heatmap.2 in the R gplots package. By default, heatmap.2 uses Euclidean measure to obtain distance matrix and complete agglomeration method for clustering.

Mentions: For a more comprehensive understanding of the interaction between NOD2- and TLR4-mediated signaling, we performed whole exon NexGen RNA sequencing of macrophages from WT and NOD2 KO mice treated with LPS alone or with both LPS and MDP together. Clustering analysis of the sequencing data involving 17484 genes (Fig. 2) shows that in WT macrophages, MDP and LPS stimulated different sets of genes (compare Groups 5 and 1 against Group 6). MDP treatment inhibited many of a gene induced by LPS while also stimulated the expression of numerous others (compare Group 2 against Group 1). Strikingly, in the absence of NOD2, macrophages were spontaneously and broadly activated, which were strongly suppressed by LPS treatment (compare Group 3 to Group 8), again demonstrating a mutually restrictive relationship between the two signaling pathways.


A novel crosstalk between TLR4- and NOD2-mediated signaling in the regulation of intestinal inflammation.

Kim H, Zhao Q, Zheng H, Li X, Zhang T, Ma X - Sci Rep (2015)

Clustering analysis of RNAseq profiling in WT vs NOD2 KO macrophages.RNA samples from WT and NOD2 KO macrophages treated with MDP or LPS or both were subjected to NexGen RNA-sequencing (whole exon). Genes of low expressions (RPKM <0.0) were filtered out. The RPKM values were further normalized per gene over all samples, to be specific, for each gene the mean and standard deviation (stddev) of RPKM over all samples were calculated, and the RPKM was linearly transformed using the formula (rpkm-mean)/stddev. The heatmap was then generated by heatmap.2 in the R gplots package. By default, heatmap.2 uses Euclidean measure to obtain distance matrix and complete agglomeration method for clustering.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495563&req=5

f2: Clustering analysis of RNAseq profiling in WT vs NOD2 KO macrophages.RNA samples from WT and NOD2 KO macrophages treated with MDP or LPS or both were subjected to NexGen RNA-sequencing (whole exon). Genes of low expressions (RPKM <0.0) were filtered out. The RPKM values were further normalized per gene over all samples, to be specific, for each gene the mean and standard deviation (stddev) of RPKM over all samples were calculated, and the RPKM was linearly transformed using the formula (rpkm-mean)/stddev. The heatmap was then generated by heatmap.2 in the R gplots package. By default, heatmap.2 uses Euclidean measure to obtain distance matrix and complete agglomeration method for clustering.
Mentions: For a more comprehensive understanding of the interaction between NOD2- and TLR4-mediated signaling, we performed whole exon NexGen RNA sequencing of macrophages from WT and NOD2 KO mice treated with LPS alone or with both LPS and MDP together. Clustering analysis of the sequencing data involving 17484 genes (Fig. 2) shows that in WT macrophages, MDP and LPS stimulated different sets of genes (compare Groups 5 and 1 against Group 6). MDP treatment inhibited many of a gene induced by LPS while also stimulated the expression of numerous others (compare Group 2 against Group 1). Strikingly, in the absence of NOD2, macrophages were spontaneously and broadly activated, which were strongly suppressed by LPS treatment (compare Group 3 to Group 8), again demonstrating a mutually restrictive relationship between the two signaling pathways.

Bottom Line: Specifically, NOD2 is able to sense the intensity of TLR4-mediated signaling, resulting in either synergistic stimulation of Interluekin-12 (IL-12) production when the TLR signaling intensity is low; or in the inhibition of IL-12 synthesis and maintenance of intestinal mucosal homeostasis when the TLR signaling intensifies.Additionally, in contrast to the dogma, we find that the major Crohn's disease-associated NOD2 mutations could cause a primarily immunodeficient phenotype by selectively impairing TLR4-mediated IL-12 production and host defense.To restore the impaired homeostasis would be a way forward to developing novel therapeutic strategies for inflammatory bowel diseases.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology and School of Life Sciences &Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China 200240.

ABSTRACT
Although Toll-like receptor 4 (TLR4)- and nucleotide-binding oligomerization domain 2 (NOD2)-mediated signaling mechanisms have been extensively studied individually, the crosstalk between them in the regulation of intestinal mucosal defense and tissue homeostasis has been underappreciated. Here, we uncover some novel activities of NOD2 by gene expression profiling revealing the global nature of the cross-regulation between TLR4- and NOD2-mediated signaling. Specifically, NOD2 is able to sense the intensity of TLR4-mediated signaling, resulting in either synergistic stimulation of Interluekin-12 (IL-12) production when the TLR signaling intensity is low; or in the inhibition of IL-12 synthesis and maintenance of intestinal mucosal homeostasis when the TLR signaling intensifies. This balancing act is mediated through receptor-interacting serine/threonine kinase 2, and the transcriptional regulator CCAAT/enhancer-binding protein α (C/EBPα) via its serine 248 phosphorylation by Protein Kinase C. Mice deficient in C/EBPα in the hematopoietic compartment are highly susceptible to chemically induced experimental colitis in an IL-12-dependent manner. Additionally, in contrast to the dogma, we find that the major Crohn's disease-associated NOD2 mutations could cause a primarily immunodeficient phenotype by selectively impairing TLR4-mediated IL-12 production and host defense. To restore the impaired homeostasis would be a way forward to developing novel therapeutic strategies for inflammatory bowel diseases.

No MeSH data available.


Related in: MedlinePlus