Sialic acid is a critical fetal defense against maternal complement attack
Markus Abeln, … , Anja Münster-Kühnel, Birgit Weinhold
Markus Abeln, … , Anja Münster-Kühnel, Birgit Weinhold
Published November 1, 2018
Citation Information: J Clin Invest. 2019;129(1):422-436. https://doi.org/10.1172/JCI99945.
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Research Article Immunology Reproductive biology

Sialic acid is a critical fetal defense against maternal complement attack

Abstract

The negatively charged sugar sialic acid (Sia) occupies the outermost position in the bulk of cell surface glycans. Lack of sialylated glycans due to genetic ablation of the Sia-activating enzyme CMP–sialic acid synthase (CMAS) resulted in embryonic lethality around day 9.5 post coitum (E9.5) in mice. Developmental failure was caused by complement activation on trophoblasts in Cmas–/– implants and was accompanied by infiltration of maternal neutrophils at the fetal-maternal interface, intrauterine growth restriction, impaired placental development, and a thickened Reichert’s membrane. This phenotype, which shared features with complement receptor 1-related protein Y (Crry) depletion, was rescued in E8.5 Cmas–/– mice upon injection of cobra venom factor, resulting in exhaustion of the maternal complement component C3. Here we show that Sia is dispensable for early development of the embryo proper but pivotal for fetal-maternal immune homeostasis during pregnancy, i.e., for protecting the allograft implant against attack by the maternal innate immune system. Finally, embryos devoid of cell surface sialylation suffered from malnutrition due to inadequate placentation as a secondary effect.

Authors

Markus Abeln, Iris Albers, Ulrike Peters-Bernard, Kerstin Flächsig-Schulz, Elina Kats, Andreas Kispert, Stephen Tomlinson, Rita Gerardy-Schahn, Anja Münster-Kühnel, Birgit Weinhold

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Figure 2

Cmas–/– mice exhibit IUGR and extraembryonic developmental deficits.

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Cmas–/– mice exhibit IUGR and extraembryonic developmental deficits. (A...
(A) H&E-stained sagittal paraffin sections of uteri at E6.5, E7.5, and E8.5. Insets show mesenchymal ME cells migrating from posterior to anterior. H, heart; S, somite. Scale bars: 12.5 μm (insets). Images are representative of at least 3 embryos within the uterus for each genotype and time point. (B) Mean fetal size as measured by the sum of the areas of the amniotic cavity, exocoelomic cavity, ectoplacental cavity, and embryo proper (μm2/105). For a schematic overview of the measured areas, see Supplemental Figure 5. E6.5 (control, n = 4; Cmas–/–, n = 5), E7.5 (control, n = 4; Cmas–/–, n = 4), E8.5 (control, n = 6; Cmas–/–, n = 7). Error bars indicate SD. Statistical analyses were performed by Student’s t test (*P < 0.05). (C) Immunohistochemical detection of cytokeratin-8 as a marker for trophoblast cells on sagittal paraffin sections of E8.5 uteri. TGC and the CP are indicated by arrows, and internal trophoblasts of the EPC are represented by arrowheads. The border of the EPC is marked by dotted lines. Images are representative of n = 3 embryos for each genotype. (D) Collagen IV and laminin indirect immunofluorescence staining on sagittal paraffin sections of uteri at E8.5 to visualize RM (arrow) and parietal endoderm (arrowheads). Nuclei stained with DAPI are shown in white. Images are representative of n = 3 embryos for each genotype.