Objective: To elucidate the mechanism by which embryo-resorption was enhanced by pathogenic CpG ODN motif in abortion-prone CBA/J x DBA/2 model and to develop a counter strategy for normal pregnancy outcome. Methods: This is an animal model-based study. Abortion-prone model is established by CBA/J x DBA/2. An infection was mimicked by CpG ODN injection. Results: Embryo-resorption was readily induced by CpG ODN in low doses of CpG ODN (similar to 25 mu g/dam) when intraperitoneally (IP) injected on gestational day(gd) 6.5 in male DBA/2 mated CBA/J female mice. A more modest decline in Progesterone(P4), but not Estrogen(E2) was observed after exposure to CpG ODN in the model. P4 supplement fail to improve pregnancy outcomes, even at pharmocology dose. CpG ODN-induced fetal resorption is prevented by the treatment of anti-F4/80 or by that of anti-TNF alpha. In the implantation sites, the treatment of anti-F4/80 inhibits the increase both of F4/80(+) macrophage proportion and TNF-alpha expression level which are induced by CpG ODN. The anti-TNF alpha treatment also recovers CpG ODN-induced reduction of CD4(+)Foxp3(+) T cells. Conclusion: Circulating P4 is not responsible for the process by which CpG ODN-induced embryonic resorption in an abortion-prone mice. Macrophage depletion and TNF-alpha inhibition are really noteworthy for CpG ODN-induced pregnancy disruption. (C) 2015 Elsevier Inc. All rights reserved.