Excessive TLR9 signaling contributes to the pathogenesis of spontaneous abortion through impairment of Treg cell survival by activation of Caspase 8/3

Abstract

Background: The pregnant uterine microenvironment is repleted with Toll-like receptors (TLRs), however, their roles of these receptors in establishing tolerance to growing fetus are largely unknown.

Result: Decidual TLR1, TLR3, TLR4, TLR8 and TLR9 gene expressions were significantly over-expressed in patients of spontaneous abortion compared with elective abortion with normal pregnancy. In particular, the expression of TLR4 and TLR9 mRNA was considerably higher than that of remaining TLRs. We mimic TLR9 signal with combination of its pathogenic ligand CpG ODN and antagonists ODN in a well-established abortion-prone CBA/J×DBA/2 model. CpG ODN dramatically boosted fetal loss and lowered the proportion of Regulatory cells (Treg cells) in vivo. CpG ODN directly triggered the impaired survival and increased activity of Caspase 8/3 of Treg cells in vitro. These effects were blocked by antagonist ODN.

Conclusion: Excessive TLR9 signaling contributed to maternal-fetal tolerance disruption via an effect on Treg cell survival by activation of Caspase 8/3.

Keywords: Caspase 3; Caspase 8; Regulatory T cells; Spontaneous abortion; Survival; Toll like receptor 9.