Regulation of recurrent spontaneous abortion by macrophage polarization through the CTRP6/PPAR-γ/NF-κB pathway and reprogramming glycolysis

The polarization of macrophages is closely related to immune homeostasis and maternal-fetal immune tolerance, and plays indispensable roles in the pathogenesis of recurrent spontaneous abortion (RSA). The role of aberrant macrophage polarization in RSA has been explored by our and others’ studies; however, the regulatory factors that participate in macrophage polarization during pregnancy have not been fully elucidated. We previously confirmed the proinflammatory effect of C1q and tumor necrosis factor-related protein 6 (CTRP6) in polycystic ovarian syndrome and the regulatory effect of CTRP6 on inflammatory factors in macrophages has been demonstrated. Herein, we aimed to investigate whether CTRP6 participates in the development of RSA by regulating macrophage polarization. Results from patients’ decidual samples indicated that CTRP6 was elevated in RSA patients by immunohistochemical and western blot analyses, and immunofluorescence analysis indicated that the expression of CTRP6 was positively correlated with CD86 + macrophages in decidual tissues. In vitro experiments indicated that CTRP6 could facilitate M1 macrophage activation and finally have an impact on the invasion and migration ability of trophoblasts. Mechanistically, CTRP6 could mediate macrophage polarization through interacting with PPAR-γ and regulating PPAR-γ/NF-κB pathway, which was associated with the activation of glycolysis. In addition to silencing CTRP6, PPAR-γ agonist (GW1929) inhibited the M1 polarization of macrophages and rescued embryo absorption in vivo . Taken together, these results demonstrate that CTRP6/PPAR-γ/NF-κB pathway may participate in M1 macrophage polarization through regulating reprogramming glycolysis, thus playing an important role in the pathogenesis of RSA.