The monosialoganglioside GM1a protects trophoblasts, erythrocytes and endothelial cells against complement attack

Wedekind, H.; Beimdiek, J.; Rossdam, C.; Kats, E.; Wittek, V.; Schumann, L.; Tiede, A.; Buettner, F. F. R.; Weinhold, B.; Muenster-Kuehnel, A.; Abeln, M.

doi:10.1101/2022.01.24.477475

bioRxiv · 10.1101/2022.01.24.477475

The monosialoganglioside GM1a protects trophoblasts, erythrocytes and endothelial cells against complement attack

Wedekind, H.·Beimdiek, J.·Rossdam, C.·Kats, E.·Wittek, V.·Schumann, L.·Tiede, A.·Buettner, F. F. R.·Weinhold, B.·Muenster-Kuehnel, A.·Abeln, M.

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Abstract

The complement system is a part of the innate immune system in the fluid phase and efficiently eliminates pathogens. However, its activation requires tight regulation on the host cell surface in order not to compromise cellular viability. Previously, we showed that loss of placental cell surface sialylation in mice in vivo leads to a maternal complement attack at the fetal-maternal interface, ultimately resulting in loss of pregnancy. To gain insight into the regulatory function of sialylation in complement activation, we here generated trophoblast stem cells devoid of sialylation, which also revealed complement sensitivity and cell death in vitro. Glycolipid-analysis by xCGE-LIF allowed us to identify the monosialoganglioside GM1a as a key element of cell surface complement regulation. Exogenously administered GM1a integrated into the plasma membrane of trophoblasts, dramatically increased binding of complement factor H and was sufficient to protect the cells from complement attack and cell death. Furthermore, GM1a treatment rescued sensitized human erythrocytes and endothelial cells from complement attack in a concentration dependent manner. This study demonstrates for the first time the complement regulatory potential of exogenously administered gangliosides and paves the way for sialoglycotherapeutics as a novel substance class for membrane-targeted complement regulators. Key pointsO_LIThe naturally occurring sialic acid containing glycosphingolipid GM1a is a potent regulator of complement activation on mammalian trophoblast, erythrocyte and endothelial cell surfaces. C_LIO_LIIncorporated GM1a recruits complement factor H and thus could represent a novel membrane-targeted complement therapeutic. C_LI

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Wedekind, H., Beimdiek, J., Rossdam, C., Kats, E., Wittek, V., Schumann, L., Tiede, A., Buettner, F. F. R., Weinhold, B., Muenster-Kuehnel, A., Abeln, M.. 2022-01-24. The monosialoganglioside GM1a protects trophoblasts, erythrocytes and endothelial cells against complement attack. https://doi.org/10.1101/2022.01.24.477475

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