The role of C5a in reproductive impairment in the mouse and human

Abstract

Adequate dietary folate is essential for a healthy pregnancy. Folate deficiency during pregnancy has been shown to contribute to foetal demise, growth retardation, craniofacial, cardiovascular, and neural tube defects, and numerous other congenital abnormalities. The present study aimed to determine whether the complement factor C5a contributes to folate-deficiency induced reproductive impairment, given that recent investigations have demonstrated that C5a can contribute to pathology in both antibody-dependent and -independent models of pregnancy loss. Administration of a folate-deficient diet (FDD) to wildtype mice resulted in poor fertility, reduced birth weights, and a high incidence of foetal loss. In contrast, C5a receptor knockout (C5aR KO) mice were resistant to foetal loss induced by a FDD, with a comparable incidence of resorption to mice administered a folate replete diet. C5aR-deficient mice on a FDD had significantly reduced birth weights and a very high prevalence of neural tube defects (40%)—a much higher frequency than FDD-fed wildtype mice. This observation suggests that in the presence of C5a, otherwise non-viable embryos from folate-deficient dams are rescued, resulting in an increased frequency of major birth defects. We also studied the expression of complement in human placenta. Placentas from growth restricted babies exhibited significant placental deposition of the upstream complement factor C3 compared to healthy controls. Intriguingly, when foetal growth restriction was associated with preeclampsia, an upregulation of placental C5aRs was additionally observed. These results suggest a complex role for the complement system and for C5a in foetal health and survival.