Immunomodulation of peripheral blood NK cells by sialic acid expressed on syncytialized BeWo cells

Preeclampsia (PE) is characterized by placental dysfunction and a systemic inflammatory state. This study investigated how hypoxia-inducible factor (HIF)-driven changes in sialic acid expression on syncytialized BeWo cells. Then we study the sialic acid modulation of peripheral natural killer (pNK) cell activity. Using a syncytialized BeWo cell model, chemical hypoxia was induced with DMOG to stabilize HIF-1α/HIF-2α. This HIF activation significantly reduced the expression of terminal mannose, α-2,3- and α-2,6-linked sialic acid. In a Co-culture syncytialized BeWo cells suppressed IFN-ɣ production in pNK cells, an effect most pronounced in the immunoregulatory CD56bright subset. Furthermore, this suppression was reversed by enzymatic removal of sialic acid (sialidase treatment), confirming its direct inhibitory role. Paradoxically, proinflammatory cytokines such as TNF-α or serum from PE patients significantly increased sialic acid expression on syncytialized BeWo cells. In parallel, soluble sialic acid directly stimulated IFN-ɣ production in pNK cells. Our in vitro findings lead us to propose a model in which HIF-driven sialic acid loss on the syncytiotrophoblast may represent a novel mechanism contributing to maternal immune activation in preeclampsia. This hypothesized pathway could potentially link placental isquemia/reperfusion to NK cell activation and systemic inflammation.