Recombinant adiponectin alleviates abortion in mice by regulating Th17/Treg imbalance via p38MAPK-STAT5 pathway.

Recurrent spontaneous abortion is associated with abnormal maternal tolerance to the semi-allogenic fetus, wherein the Th17/Treg axis plays a crucial role. Adiponectin (APN) is an adipocytokine that is shown to be a novel negative T-cell regulator and induce immune tolerance. The CBA/JxDBA/2 mating was used as an abortion-prone model to investigate whether the addition of recombinant adiponectin (rAPN) improves the pregnancy outcome. Recombinant adiponectin therapy reduced the abortion rate in abortion-prone model. It skewed the ability of serum cytokine production toward a Treg bias and induced APN production. Flow cytometry revealed that rAPN administration expanded the splenic CD4(+)CD25(+) regulatory T-cell (Treg) population and reduced the Th17 cell populations in CBA/JxDBA/2 matings. RT-PCR revealed that rAPN administration induced the expression of AdipoR1 and AdipoR2 mRNA at the maternofetal interface. Recombinant adiponectin administration induced FoxP3 and reduced ROR gamma t expressions at the maternofetal interface. In vitro experiment also showed that rAPN treatment enhanced the FoxP3 mRNA and protein expression and decreased the ROR gamma t expression in splenic lymphocytes of abortion-prone mice. Blocking the different signal transduction pathways downstream of APN, p38MAPK inhibitor (SB203580) and STAT5 inhibitor (Pimozide) could abrogate the regulatory effect of rAPN on FoxP3 and ROR gamma t expression, while STAT3 inhibitor (Stattic) and AMPK inhibitor (p5499) did not exert any influence. Thus, the current results demonstrated that rAPN therapy improves pregnancy outcome in a murine model of abortion by expanding the Treg cell population and function and decreasing the Th17 cell population and function via a p38MAPK-STAT5 pathway. Adiponectin, which is essential for lipid metabolism and homeostasis, is beneficial for pregnancy outcome through improving Th17 and Treg populations; the process is associated with the activation of p38MAPK-STAT5 pathway.