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

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-α (TNF-α) 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-α 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-α production, and consequent adverse pregnancy outcomes.