Metabolic Reprogramming Driven by Trophoblasts and Decidual XCR1⁺PMN-MDSC Crosstalk Controls Adverse Outcomes...

Trophoblast-immune cell communication is crucial during pregnancy, with impairments linked to adverse outcomes. The accumulation of decidual polymorphonuclear myeloid-derived suppressor cells (dPMN-MDSCs) in the third trimester is vital for fetal development. This study presents a novel crosstalk mechanism between trophoblasts and dPMN-MDSCs that improves adverse outcomes associated with advanced maternal age (AMA). A specific dPMN-MDSC population with high X-C motif chemokine receptor 1 (XCR1) expression is identified, which interacts with trophoblasts through X-C motif chemokine ligand 1 (XCL1) during the third trimester. Spontaneous fetal growth restriction observed in AMA and pregnant Xcr1^-/- mice is correlated with the disruption of this interaction. Mechanistically, the deficiency in XCL1-XCR1 expression reduces nuclear FOXO1 levels, thereby impairing the transcription of FOXO1-driven oxidative phosphorylation genes in decidual XCR1⁺PMN-MDSCs. Restoring the expression of XCL1-XCR1 or FOXO1 in dPMN-MDSCs mitigates this effect. Crucially, their adoptive transfer or treatment with XCL1/Oltipraz rescues the delayed fetal growth linked to impaired decidual XCR1⁺PMN-MDSCs and metabolic imbalance. Our findings highlight the importance of trophoblast-dPMN-MDSC communication via the XCL1-XCR1 axis, proposing metabolic reprogramming of dPMN-MDSCs as a potential immunotherapeutic strategy for AMA-related adverse outcomes.