Complement component C4a binds to oxytocin and modulates plasma oxytocin concentrations and social behavior in male mice

Oxytocin (OT) is a hormone with a short half-life that is released from the posterior pituitary gland into the bloodstream. It plays an important role in childbirth, breastfeeding, and social behavior in humans and animals. However, the endogenous OT system, including plasma OT pharmacokinetics, is not fully understood. In this study, we used a click chemistry probe to discover a novel OT-binding protein in human serum and identified C4a, a peptidase-cleaved fragment of complement component 4 (C4). A direct association between OT and C4a was also confirmed. Upon knocking out Slp gene, which is one of the two mouse C4 genes, the level of free form of plasma OT was higher in Slp knockout (Slp^-/-) mice than in wild-type (Slp^+/+) mice after intraperitoneal OT injection. In addition, open-field tests revealed that social interactions were higher in Slp^-/- mice than Slp^+/+ mice. An in vitro blood-brain barrier model showed that C4a neither inhibited nor accelerated receptor for advanced glycation end-product (RAGE)-dependent brain transport in OT. Our data validate the novel concept that C4a with OT-binding capacity can alter the dynamics of the free form of OT concentrations in the plasma, which may disturb the availability of OT to the brain, resulting in an interruption of OT-associated social behavior.