Cyclophilin A as a Pro-Inflammatory Factor Exhibits Embryotoxic and Teratogenic Effects during Fetal Organogenesis

The precise balance of Th1, Th2, and Th17 cytokines is a key factor in successful pregnancy and normal embryonic development. However, to date, not all humoral factors that regulate and influence physiological pregnancy have been completely studied. Our data here pointed out cyclophilin A (CypA) as the adverse pro-inflammatory factor negatively affecting fetal development and associated with pregnancy complications. In different mouse models in vivo, we demonstrated dramatic embryotoxicity and teratogenicity of increased CypA levels during pregnancy. Using generated transgenic models, we showed that CypA overexpression in fetal tissues induced the death of all transgenic fetuses and complete miscarriage. Administration of recombinant human CypA in a high dose to pregnant females during fetal organogenesis (6.5-11.5 dpc) exhibited teratogenic effects, causing severe defects in the brain and bone development that could lead to malformations and postnatal behavioral and cognitive disorders in the offspring. Embryotoxic and teratogenic effects could be mediated by CypA-induced up-regulation of M1 macrophage polarization via activation of the STAT1/3 signaling pathways. Here, we propose secreted CypA as a novel marker of complicated pregnancy and a therapeutic target for the correction of pregnancy complications.

Automated summary

This study identified CypA as an adverse pro-inflammatory factor negatively affecting fetal development and associated with pregnancy complications. The researchers demonstrated that increased CypA levels during pregnancy caused dramatic embryotoxicity and teratogenicity in different mouse models. Using transgenic models, they showed that CypA overexpression in fetal tissues led to fetal death and complete miscarriage. Furthermore, administering high doses of recombinant human CypA to pregnant females resulted in severe defects in brain and bone development, potentially leading to postnatal behavioral and cognitive disorders in the offspring. The embryotoxic and teratogenic effects were mediated by CypA-induced up-regulation of M1 macrophage polarization via activation of the STAT1/3 signaling pathways. These findings suggest that CypA could serve as a novel marker for complicated pregnancy and a therapeutic target for the correction of pregnancy complications.