Antiphospholipid antibodies inhibit the migration and invasion of trophoblast cells by suppressing the JNK/C-Jun/MMP1 signaling pathway.

backgroundAntiphospholipid syndrome (APS) is an autoimmune disease primarily manifested by recurrent thrombosis and pregnancy-related complications. The migration and invasion abilities of trophoblast cells play a crucial role in maintaining normal pregnancy. It is now increasingly recognized that adverse pregnancy outcomes in APS are associated with the disruption of trophoblast function by aPL (antiphospholipid antibodies), rather than thrombotic occlusion of the placental vasculature. Therefore, this article aimed to explore the potential mechanisms by which aPL affect trophoblast cell function.

methodAn APS cell model was established in the HTR-8 trophoblast cell line, followed by RNA sequencing to identify key genes involved in trophoblast cell function. To explore the underlying mechanisms, we employed quantitative real-time PCR, Western blotting, immunohistochemistry, ELISA, plasmid transfection and KEGG pathway enrichment analysis. Functional assays, including migration and invasion tests, were conducted to evaluate trophoblast cell ability. Clinical samples were collected, and the expression levels of target molecules in serum were quantified using ELISA. Additionally, an APS animal pregnancy model was developed to assess pregnancy loss rates and analyze the expression of specific target genes in the placenta.

resultsSequencing analysis revealed significant downregulation of MMP1 in the APS model, confirmed by qPCR and Western blotting. Correspondingly, migration and invasion of HTR-8 cells were impaired in the APS group, but MMP1 overexpression restored trophoblast cell function. Serum MMP1 levels were lower in APS patients than in controls. In the animal pregnancy model, the APS group exhibited higher pregnancy loss, with placental immunohistochemistry confirming decreased MMP1 expression. KEGG enrichment analysis of differentially expressed genes between the NC and APS groups revealed a significant difference in the MAPK pathway, with P-JNK showing the most notable reduction. C-Jun, a downstream regulator of JNK, also decreased and modulated MMP1 expression. Notably, Anisomycin treatment increased P-C-Jun, upregulated MMP1, and enhanced trophoblast migration and invasion.

conclusionAPL downregulated MMP1 expression by suppressing the JNK/C-Jun signaling pathway in trophoblast cells, thereby reducing their migratory and invasive capabilities. This represent a potential pathogenic mechanism contributing to adverse pregnancy outcomes in APS patients, highlighting possible therapeutic targets for intervention in APS management.