The role of TLR2/MyD88/NF-κB pathway-mediated macrophage M1 polarization in recurrent spontaneous abortion associated with antiphospholipid syndrome

The pathogenesis of recurrent miscarriage (RSA) is highly complex. Studies indicate that abnormal polarization of decidual macrophages is critical for pregnancy failure. The aim of this research is to investigate the function of M1 polarization of macrophages in antiphospholipid syndrome (APS)-associated RSA and the potential mechanisms involved. Macrophages from decidual tissues was assessed by flow cytometry. In vitro, THP-1 monocytes were induced by anti-β2GPI/β2GPI and M1 polarization ratio was quantified. Pro-inflammatory cytokine levels were measured by ELISA, and TLR2/MyD88/NF-κB pathway proteins were analyzed via Western blot. To examine the impact of M1 macrophages on epithelial-mesenchymal transition (EMT), migration, and invasion of trophoblasts, THP-1 and HTR-8/SVneo cells were co-cultured. The NF-κB Inhibitor JSH-23 was then applied to treat THP-1 cells to assess its impact on M1 macrophage-induced trophoblast behavior. An aPL-induced abortion mice model was constructed to determine whether blocking NF-κB could inhibit decidual macrophage M1 polarization and improve pregnancy outcomes. In RSA-aPL patients, decidual M1 macrophages proportion and TLR2 expression were significantly increased, and the MyD88/NF-κB pathway was activated. Anti-β2GPI/β2GPI triggered the differentiation of THP-1 cells into M1 macrophages and activated the TLR2/MyD88/NF-κB pathway, while silencing TLR2 suppressed the M1 polarization. Furthermore, M1-polarized macrophages inhibited EMT, migration, and invasion of HTR-8/SVneo cells, which could be reversed by JSH-23. Moreover, JSH-23 reduced M1 polarization of decidual macrophages in aPL-induced abortion mice, improving pregnancy outcomes. In conclusion, this study confirms that activation of the TLR2/MyD88/NF-κB pathway promotes the M1 macrophage polarization and has a significant impact on APS-associated RSA.

Antiphospholipid syndrome; Decidual macrophages; NF-κB; Recurrent miscarriage; TLR2.