Fractalkine (Chemokine CX3CL1) Signaling During Placentation and Placental Function

Precise postimplantation regulation of placental development with trophoblast invasion of uterine spiral arteries and the generation of low-resistance circulation within the utero-fetal unit are crucial for the further development of pregnancy. Cytokines, including chemokines, are crucial for ensuring placental function throughout pregnancy. The CX3CL1 chemokine (fractalkine), occurring in its membrane-bound form and as a soluble chemokine (sCX3CL1), acts on its sole receptor, namely, CX3CR1, creating a signaling axis that orchestrates the balance of cellular interactions, immune responses, and tissue remodeling needed at every stage of a healthy pregnancy. CX3CL1/CX3CR1 signaling is characterized by the activation of several downstream signaling cascades that interact with numerous pathways, coordinate with other receptors and modulate the expression of relevant genes. This review presents the current state of knowledge regarding the role of CX3CL1 and its interaction with CX3CR1 in establishing placental homeostasis during placentation, and it discusses the contribution of disturbances in this interaction to placental dysfunction. These disturbances are part of the pathomechanisms of specific pregnancy complications, including preeclampsia (PE) and diabetes. The potential to target the CX3CL1/CX3CR1 axis via therapeutic intervention at the level of the placenta in PE- and diabetes-complicated pregnancy is the subject of ongoing research.