A defective lysophosphatidic acid-autophagy axis increases miscarriage risk by restricting decidual macrophage residence

Massive infiltrated and enriched decidual macrophages (dM phi) have been widely regarded as important regulators of maternal-fetal immune tolerance and trophoblast invasion, contributing to normal pregnancy. However, the characteristics of metabolic profile and the underlying mechanism of dM phi residence remain largely unknown. Here, we observe that dM phi display an active glycerophospholipid metabolism. The activation of ENPP2-lysophosphatidic acid (LPA) facilitates the adhesion and retention, and M2 differentiation of dM phi during normal pregnancy. Mechanistically, this process is mediated through activation of the LPA receptors (LPAR1 and PPARG/PPAR gamma)-DDIT4-macroautophagy/autophagy axis, and further upregulation of multiple adhesion factors (e.g., cadherins and selectins) in a CLDN7 (claudin 7)-dependent manner. Additionally, poor trophoblast invasion and placenta development, and a high ratio of embryo loss are observed in Enpp2(+/-), lpar1(-/-) or PPARG-blocked pregnant mice. Patients with unexplained spontaneous abortion display insufficient autophagy and cell residence of dM phi. In therapeutic studies, supplementation with LPA or the autophagy inducer rapamycin significantly promotes dM phi autophagy and cell residence, and improves embryo resorption in Enpp2(+/-) and spontaneous abortion mouse models, which should be dependent on the activation of DDIT4-autophagy-CLDN7-adhesion molecules axis. This observation reveals that inactivation of ENPP2-LPA metabolism and insufficient autophagy of dM phi result in resident obstacle of dM phi and further increase the risk of spontaneous abortion, and provides potential therapeutic strategies to prevent spontaneous abortion.

Automated summary

Decidual macrophages (dMφ), important regulators of maternal-fetal immune tolerance and trophoblast invasion during pregnancy, display an active glycerophospholipid metabolism and their adhesion and retention, as well as M2 differentiation, are facilitated by the activation of ENPP2-lysophosphatidic acid (LPA). This process involves the activation of LPA receptors, mediated through the DDIT4-macroautophagy/autophagy axis, leading to upregulation of multiple adhesion factors and poor trophoblast invasion. Supplementation with LPA or autophagy inducer rapamycin improves dMφ autophagy and cell residence, preventing spontaneous abortion.