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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

Role of C/EBPα and IL-12 in TNBS-induced colitis.(a) TNBS colitis was induced in WT and cebpα KO mice. MDP was administered i.p. on days –3, –2, and –1 (n = 9/group). Anti-IL12 antibody (b, c) or anti-IL-23 (c), or the control IgG were administrated on days 0, and 2 (n = 4/group). Mean body weight of three independent experiments with SE is represented. (c) H&E-staining of colonic tissues of NBS-, MDP- or anti-IL-12-treated mice harvested on day 4 are shown in 100x magnification showing massive infiltration of mononuclear cells as well as destruction of crypt architecture. (d) Histology scores of the colonic tissues harvested on day 4. **p < 0.01. (f) Sera from the mice were collected on day 4 and analyzed for cytokine production by ELISA (IL-12 and IL-23p40). **p < 0.01.
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f7: Role of C/EBPα and IL-12 in TNBS-induced colitis.(a) TNBS colitis was induced in WT and cebpα KO mice. MDP was administered i.p. on days –3, –2, and –1 (n = 9/group). Anti-IL12 antibody (b, c) or anti-IL-23 (c), or the control IgG were administrated on days 0, and 2 (n = 4/group). Mean body weight of three independent experiments with SE is represented. (c) H&E-staining of colonic tissues of NBS-, MDP- or anti-IL-12-treated mice harvested on day 4 are shown in 100x magnification showing massive infiltration of mononuclear cells as well as destruction of crypt architecture. (d) Histology scores of the colonic tissues harvested on day 4. **p < 0.01. (f) Sera from the mice were collected on day 4 and analyzed for cytokine production by ELISA (IL-12 and IL-23p40). **p < 0.01.

Mentions: To determine definitively whether MDP’s rescuing effects on TNBS-induced colitis13 were dependent on C/EBPα, we used the conditional C/EBPα-deficient mice in which hematopoietic cell-specific deletion of the cebpa gene is initiated by the administration of poly I-C36. As shown in Fig. 7a, compared to WT mice, C/EBPα-deficient mice were more susceptible to colitis-associated weight loss. They also displayed more severe colonic tissue inflammation induced by TNBS administration (Fig. 7d,e). Crucially, MDP’s ability to protect mice from TNBS-induced colitis was completely lost in C/EBPα-deficient mice (Fig. 7a). Further, we tested the effect of neutralizing antibodies against IL-12 and IL-23, respectively. Compared with the control IgG-treated mice, colitis was completely rescued by the IL-12-neutralizing antibody in WT and C/EBPα-deficient mice (Fig. 7b) but not by anti-IL-23 (Fig. 7c), consistently with the degrees of serum levels of IL-12 (Fig. 7f).


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)

Role of C/EBPα and IL-12 in TNBS-induced colitis.(a) TNBS colitis was induced in WT and cebpα KO mice. MDP was administered i.p. on days –3, –2, and –1 (n = 9/group). Anti-IL12 antibody (b, c) or anti-IL-23 (c), or the control IgG were administrated on days 0, and 2 (n = 4/group). Mean body weight of three independent experiments with SE is represented. (c) H&E-staining of colonic tissues of NBS-, MDP- or anti-IL-12-treated mice harvested on day 4 are shown in 100x magnification showing massive infiltration of mononuclear cells as well as destruction of crypt architecture. (d) Histology scores of the colonic tissues harvested on day 4. **p < 0.01. (f) Sera from the mice were collected on day 4 and analyzed for cytokine production by ELISA (IL-12 and IL-23p40). **p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Role of C/EBPα and IL-12 in TNBS-induced colitis.(a) TNBS colitis was induced in WT and cebpα KO mice. MDP was administered i.p. on days –3, –2, and –1 (n = 9/group). Anti-IL12 antibody (b, c) or anti-IL-23 (c), or the control IgG were administrated on days 0, and 2 (n = 4/group). Mean body weight of three independent experiments with SE is represented. (c) H&E-staining of colonic tissues of NBS-, MDP- or anti-IL-12-treated mice harvested on day 4 are shown in 100x magnification showing massive infiltration of mononuclear cells as well as destruction of crypt architecture. (d) Histology scores of the colonic tissues harvested on day 4. **p < 0.01. (f) Sera from the mice were collected on day 4 and analyzed for cytokine production by ELISA (IL-12 and IL-23p40). **p < 0.01.
Mentions: To determine definitively whether MDP’s rescuing effects on TNBS-induced colitis13 were dependent on C/EBPα, we used the conditional C/EBPα-deficient mice in which hematopoietic cell-specific deletion of the cebpa gene is initiated by the administration of poly I-C36. As shown in Fig. 7a, compared to WT mice, C/EBPα-deficient mice were more susceptible to colitis-associated weight loss. They also displayed more severe colonic tissue inflammation induced by TNBS administration (Fig. 7d,e). Crucially, MDP’s ability to protect mice from TNBS-induced colitis was completely lost in C/EBPα-deficient mice (Fig. 7a). Further, we tested the effect of neutralizing antibodies against IL-12 and IL-23, respectively. Compared with the control IgG-treated mice, colitis was completely rescued by the IL-12-neutralizing antibody in WT and C/EBPα-deficient mice (Fig. 7b) but not by anti-IL-23 (Fig. 7c), consistently with the degrees of serum levels of IL-12 (Fig. 7f).

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