Dataset Information

Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls.

ABSTRACT:

Objective

To elucidate the relationship between CpG-induced activation of innate immunity and pregnancy outcome.

Design

An animal model-based study.

Setting

Academic.

Animal(s)

Pregnant nonobese diabetic (NOD) mice were compared with nonimmunodeficient mice.

Intervention(s)

We mimic toll-like receptor 9 (TLR9) activation using CpG ODN administration in pregnant wild-type (WT) and natural killer (NK) cell-deficient NOD mice.

Main outcome measure(s)

Evaluation of fetal resorption and preterm birth in pregnant mice; flow-cytometric analysis and ELISA detection.

Result(s)

CpG-induced fetal resorption or preterm birth was observed steadily only in NOD mice but not in WT mice. Concurrently, CpG treatment triggered amplification of uterine macrophages and neutrophils. Moreover, CpG induced a substantial increase of serum mouse keratinocyte-derived cytokine (mKC) and tumor necrosis factor-? (TNF-?) that were produced by uterine CD11b(+)F4/80(+) cells but not by NK or CD11b(+)Gr-1(+) cells. In addition, depletion of F4/80(+) cells abrogated a CpG-induced increase in TNF-? production and improved pregnancy outcomes in NOD mice treated with CpG.

Conclusion(s)

These results provide evidence that CpG-driven innate immune activation may lead to activation and amplification of macrophages followed by their migration to fetomaternal microenvironment, up-regulated TNF-? production, and consequent adverse pregnancy outcomes.

SUBMITTER: Sun Y

PROVIDER: S-EPMC3756663 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls.

Sun Yun Y Qin Xiaoli X Shan Bin B Wang Wenjing W Zhu Qinling Q Sharma Surendra S Wu Ji J Lin Yi Y

Fertility and sterility 20130213 6

<h4>Objective</h4>To elucidate the relationship between CpG-induced activation of innate immunity and pregnancy outcome.<h4>Design</h4>An animal model-based study.<h4>Setting</h4>Academic.<h4>Animal(s)</h4>Pregnant nonobese diabetic (NOD) mice were compared with nonimmunodeficient mice.<h4>Intervention(s)</h4>We mimic toll-like receptor 9 (TLR9) activation using CpG ODN administration in pregnant wild-type (WT) and natural killer (NK) cell-deficient NOD mice.<h4>Main outcome measure(s)</h4>Evalu ...[more]

PMID: 23414919

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Project description:Background: Epigenetic alteration of the genome has been shown to provide palliative effects in mouse models of certain human autoimmune disorders. We have investigated whether chromatin remodeling could provide protection against autoimmune diabetes in nonobese diabetic (NOD) mice. Treatment of female mice during the transition from prediabetic to diabetic stage (18-24 weeks of age) with the well-characterized histone deacetylase inhibitor, Trichostatin A (TSA) effectively reduced the incidence of diabetes and abrogated the ability of splenocytes to adoptively transfer the disease into immunodeficient NOD.scid mice. Protection against diabetes was accompanied by histone hyperacetylation in pancreas and spleen, increased frequency of CD4+ CD62L+ cells in the spleen, reduction in cellular infiltration of islets, restoration of normoglycemia and glucose-induced insulin release by beta cells. In vitro activation of splenic T lymphocytes derived from protected mice resulted in enhanced expression of IFN-gamma mRNA and protein without altering the expression of Il4, Il17, Il18, Inos, and Tnfa genes nor the secretion of IL-2, IL-4, IL-17 and TNF-alpha proteins. Consistently, expression of the transcription factor involved in Ifng transcription, Tbet/Tbx21 but not Gata3 and Rorgt, respectively required for the transcription of Il4 and Il17, was upregulated in activated splenocytes of protected mice. These data indicate that abrogation of autoimmune diabetes is associated with the selective upregulation of certain inducible genes in T lymphocytes. Microarray analysis was performed to determine the changes in global gene expression underlying abrogation of autoimmune diabetes by TSA-mediated epigenetic modulation and identified a distinct group of genes down-regulated during this process. Female NOD mice were treated subcutaneously with TSA (500 µg/Kg body weight) during the transition from prediabetic to diabetic stage (18-24 weeks of age), at weekly intervals. Since we sought to determine the modulation of global gene expression associated with long-term protection against diabetes, TSA treated mice were killed between 32 and 36 weeks of age and total RNA was extracted from uninduced splenocytes. RNA was also extracted from splenocytes of untreated mice that became diabetic and those that did not develop diabetes till 36 weeks of age. Blood glucose levels were determined weekly to monitor the glycemic condition in untreated and TSA-treated mice. To minimize the variability in gene expression among individual mice, RNA was extracted from splenocytes of 3 to 5 mice per group and pooled. Each sample was hybridized to microchips in duplicate. Female NOD mice were treated with Trichostatin A (500 µg/Kg body weight) between 18-24 weeks of age or left untreated.

Dataset Information

Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls.

Objective

Design

Setting

Animal(s)

Intervention(s)

Main outcome measure(s)

Result(s)

Conclusion(s)

Publications

Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls.

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