Sialic acid-binding immunoglobulin-like lectin-6 (SIGLEC6) is increased by hypoxia and inflammation; relevance to preeclampsia

Abstract SIGLEC6, a human-specific transmembrane receptor, is highly expressed in placenta. Our team have identified elevated SIGLEC6 in maternal circulation preceding preeclampsia and in women with preeclampsia, correlating with disease severity. This study aimed to characterise SIGLEC6 relevant to preeclampsia using human (cyto)trophoblast stem cells (hTSCs) and primary Human Umbilical Vein Endothelial Cells (HUVECs). SIGLEC6 was measured across three placental cell types by differentiating hTSCs: (cyto)trophoblasts, syncytiotrophoblasts, and extravillous trophoblasts. SIGLEC6 was expressed in all cell types and upregulated during differentiation into syncytiotrophoblasts and extravillous trophoblasts. Exposure of syncytialised hTSCs to hypoxia (1% vs 8% O₂) elevated SIGLEC6 expression (p = 0.0079), and protein secretion (p = 0.0079). Similarly, inflammatory cytokines (IL-6 or TNFα) increased SIGLEC6 expression (IL-6: p = 0.0016, and TNFα: p = 0.0015) and protein secretion (IL-6: p = 0.002, and TNFα: p = 0.01) from syncytialised hTSCs. Treatment with Brefeldin A (impairs protein trafficking) reduced SIGLEC6 secretion in cell lysates (p = 0.001) and conditioned media (p = 0.02). To evaluate functional effects, HUVECs were treated with recombinant SIGLEC6. No significant changes were observed in endothelial dysfunction markers (VCAM1, ICAM1, ET-1), pro-angiogenic factors (PlGF, VEGF) or anti-angiogenic splice variants (sFlt-1 e15a, sFlt-1 i13). SIGLEC6 expression is induced by hypoxia and inflammation in syncytialised hTSCs, but recombinant SIGLEC6 does not induce features of endothelial dysfunction observed in preeclampsia.