Immler, R.; Nadolni, W.; Franz, J. M.; Bertsch, A.; Baasch, S.; Morikis, V. A.; Kurova, A.; Borso, M.; Forne, I.; Itang, E. C. M.; Mueller-Reif, J. B.; Pruenster, M.; Wackerbarth, L. M.; Napoli, M.; Rohwedder, I.; Yevtushenko, A.; Rauer, M.; Kolben, M.; Moser, M.; Barnea, E.; Boerries, M.; Vogl, T.; Simon, S. I.; Klein, C.; Henneke, P.; Imhof, A.; Zierler, S.; Sperandio, M.

Pregnancy is a unique period regarding immune cell regulation. Within the placenta, maternal immune cells play a central role in immune surveillance and tissue remodeling. However, regulatory mechanisms of systemic immunity during pregnancy are less clear. Here, we show that neutrophil function is altered in pregnant mice (E13.5), indicated by increased slow rolling velocity and reduced adhesion. Mechanistically, PreImplantation factor (PIF), a 15 amino acid peptide which is produced by human and murine trophoblast cells of the placenta, is continuously secreted into the maternal circulation and plays a key role in modulating neutrophil function via blocking the voltage-gated potassium channel KV1.3. This resulted in impaired intracellular Ca2+ signaling and subsequently disturbance of neutrophil post-arrest modifications and a higher susceptibility to physiological shear forces in vivo and in vitro. Furthermore, PIF-mediated KV1.3 blockade impaired E-selectin-mediated release of S100A8/A9 and phagocytosis. Taken together, we have identified PIF as an important modulator of neutrophil function during pregnancy suggesting a critical role in regulating innate immune responses throughout gestation.