Fructose-1,6-bisphosphate prevents pregnancy loss by inducing decidual COX-2 ⁺ macrophage differentiation

Abstract

Decidualization is an intricate biological process in which extensive remodeling of the endometrium occurs to support the development of an implanting blastocyst. However, the immunometabolic mechanisms underlying this process are still largely unknown. We found that the decidualization process is accompanied by the accumulation of fructose-1,6-bisphosphate (FBP). The combination of FBP with pyruvate kinase M stimulated IL-27 secretion by endometrial stromal cells in an ERK/c-FOS–dependent manner. IL-27 induced decidual COX-2 + M2-like macrophage differentiation, which promotes decidualization, trophoblast invasion, and maternal-fetal tolerance. Transfer of Ptgs2 + /COX-2 + macrophages prevented fetal loss in Il27ra -deleted pregnant mice. FBP levels were low in plasma and decidual tissues of patients with unexplained recurrent spontaneous abortion. In therapeutic studies, FBP supplementation significantly improved embryo loss by up-regulation of IL-27–induced COX-2 + macrophage differentiation in a mouse model of spontaneous abortion. These findings collectively provide a scientific basis for a potential therapeutic strategy to prevent pregnancy loss.

The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss*

“…115 Moreover, there was a significant decreased accumulation of FBP in plasma and decidua from RPL patients. 115 Similarly, both the levels of IL-27 in DSCs and the percentage of COX-2 + M2-like dMφ were reduced in RPL patients, suggesting insufficient FBP-IL-27 expression and COX-2 + Mφ in the decidua of RPL patients. 115 As the rate-limiting enzymes, COX-1 and COX-2 promote the biosynthesis of prostaglandins (PGs), which are the major lipid mediators.…”

“…115 Similarly, both the levels of IL-27 in DSCs and the percentage of COX-2 + M2-like dMφ were reduced in RPL patients, suggesting insufficient FBP-IL-27 expression and COX-2 + Mφ in the decidua of RPL patients. 115 As the rate-limiting enzymes, COX-1 and COX-2 promote the biosynthesis of prostaglandins (PGs), which are the major lipid mediators. However, the potential role of COX-2/PGE2 metabolism remains to be determined in dMφ.…”

“…173 Based on our previous study, we found that exogenous injection of FBP would greatly increase the uterine and plasma levels of FBP. 115 Additionally, the COX-2 + dMφ induced by FBP prevented pregnancy loss via promoting maternalfetal immune tolerance, decidualization, and trophoblast invasion. 115 Glycolysis has been reported in the murine uterus to support decidualization and provide ATP via multiple pathways.…”

“…As found in our previous study, FBP was accumulated in DSCs during decidualization. 115 When compared to endometrial stromal cells (ESCs), there were increased PFK1 and decreased FBP1 levels in DSCs. In addition, ovarian hormones and trophoblasts were associated with this accumulation.…”

“…As shown, various metabolic biomarkers appear to be associated with the pathogenesis of RPL (eg, APOA1, FBP, IDO). 115,118,162,163 Interestingly, interventions targeting on these metabolic markers have displayed satisfactory therapeutic values for pregnancy loss in selected animal models (Table 2). Unfortunately, it remains whether these metabolic inventions are applicable in clinical scenarios.…”