NAD+ Metabolism Maintains the Homeostasis of Decidual Macrophages in Early Pregnancy

Disruption of decidual macrophage (dMφ) homeostasis is related to adverse pregnancy outcomes such as recurrent spontaneous abortion (RSA). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD⁺ salvage pathway, converts nicotinamide (NAM) to NAD⁺ precursor nicotinamide mononucleotide (NMN). Although restriction of NAD⁺ metabolism has been implicated in leading to fetal loss in pregnant mice, whether NAMPT is involved in regulating maternal-fetal maintenance and the underlying mechanism has been poorly understood. Here, we demonstrated that primary decidual macrophages from RSA patients showed decreased expression of NAMPT and impaired NAD⁺ metabolism. NAMPT^+/- mice exhibited a significant elevation in the embryonic absorption rate compared with that of wild-type (WT) mice, and adoptive transferring WT macrophages into NAMPT^+/- mice significantly ameliorated the adverse pregnancy outcome. Genetic and pharmacological interference of NAMPT disrupted the differentiation of M1 macrophages. Mechanically, deficiency of NAMPT inhibited gasdermin D (GSDMD) cleavage independently from canonical Pyroptosis. The cleaved N-terminal fragment of GSDMD functioned as a stimulus to activate the NF-κB pathway and subsequently promoted TNF-α transcription by phospho-P65 (S536). NMN replenishment ameliorated the dysregulation of M1 macrophage differentiation, the infiltration of trophoblasts, and fetal loss. Our study reveals an NAMPT-associated immunopathogenesis of early pregnancy loss and provides a new idea for the therapeutic strategy for RSA patients.