Single-cell sequencing reveals that neutrophils mediate the inflammatory response in gestational diabetes

Abstract Gestational diabetes mellitus (GDM) is a pregnancy-associated metabolic disorder characterized by insulin resistance and hyperglycemia, posing significant risks to maternal-fetal health. While placental inflammation contributes to GDM pathology, its cellular mechanisms remain incompletely understood. Leveraging public single-cell RNA sequencing (scRNA-seq) data, we constructed a cellular atlas of GDM and control placental tissues, identifying 14 transcriptionally distinct populations. Neutrophil_1 emerged as the dominant pro-inflammatory subset, exhibiting amplified interactions with macrophages and T cells that exacerbate inflammatory responses. Pseudotime trajectory analysis revealed Neutrophil_2 as a precursor state differentiating toward the Neutrophil_1 lineage through transcriptionally regulated programming. Critically, Arginine catabolism and Nicotinate/nicotinamide metabolism were found to modulate Neutrophil_1's pro-inflammatory functions. Our findings implicate pathogenic neutrophil subsets in GDM progression and nominate arginase and NAMPT inhibition as potential therapeutic strategies for mitigating neutrophil-mediated placental inflammation.