article · International Journal of Biological Sciences
Lactic acid metabolism plays an important role in establishing immune tolerance, but its function at the maternal-fetal interface during early pregnancy has been poorly understood. This research shows that lactic acid directs decidual macrophage differentiation by regulating oxidative phosphorylation and glycolysis. Depending on oxygen availability, it drives either M2 polarisation under normoxia or M1 polarisation under hypoxia. The metabolic pathway, operating via HIF-1alpha, SRC, and LDHA signalling, is directly implicated in recurrent pregnancy loss driven by decidual macrophages. In an abortion-prone mouse model, inhibiting lactic acid uptake using the MCT-1 inhibitor AZD3965 successfully rescued pregnancy. These findings identify a key metabolic mechanism governing immune cell behaviour at the maternal-fetal interface and suggest that manipulating lactic acid pathways could offer a viable therapeutic approach to treating recurrent pregnancy loss.
Recurrent pregnancy loss is a distressing condition with complex immune causes. Revealing how metabolic signals like lactic acid control immune cell behaviour in the womb helps clarify why some pregnancies fail. Identifying specific molecular pathways and testing an existing drug inhibitor in mice provides a biological foundation for developing new medical interventions to prevent miscarriage in affected individuals.
The findings point towards therapeutic development for recurrent pregnancy loss, specifically targeting the MCT-1 receptor and related signalling pathways to regulate immune tolerance. Potential users include biopharmaceutical firms and reproductive health clinicians developing miscarriage interventions. Because efficacy has been tested solely in an abortion-prone mouse model using the inhibitor AZD3965, the work represents early-stage preclinical research that requires extensive further testing before real-world clinical application.
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Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear. Herein, for the first time, we discovered that LA can trigger either M2 or M1 macrophage polarization via oxidative phosphorylation and glycolysis regulation under normoxia or hypoxia, respectively. Also, LA metabolism played a vital role in decidual macrophages-mediated recurrent pregnancy loss (RPL), through HIF-1α/SRC/LDHA pathway. Moreover, blockade of LA intake with AZD3965 (MCT-1 inhibitor) could rescue pregnancy in an abortion-prone mouse model, suggesting a potential therapeutic target in RPL. Collectively, the present study identifies the previously unknown functions of LA metabolism in the differentiation of decidual macrophages in early normal pregnancy and RPL, and provides a potential therapeutic strategy in RPL by manipulating decidual macrophages' functions through LA metabolic pathway.
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DOI: 10.7150/ijbs.67816
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