Maternal stress shapes offspring innate immunity via milk leptin

Early-life stress (ELS) leaves a persistent inflammatory imprint, but how parental physiology shapes offspring immune development remains unclear. Using the limited bedding and nesting (LBN) mouse model of ELS, we show that maternal stress alters offspring immune homeostasis through changes in maternal milk composition, rather than reduced maternal care. Maternal stress decreases leptin levels in milk and pup circulation, blunting the neonatal leptin surge and leading to persistent neutrophilia and altered neutrophil function. Glucocorticoid administration to dams lowers pup plasma leptin and recapitulates the endocrine and immunological phenotype of LBN, without reproducing the associated maternal changes in behavior. Conversely, leptin administration to pups restores immune homeostasis, while biparental care normalizes maternal stress physiology, restores leptin levels and prevents offspring neutrophilia. These findings identify maternal milk leptin as a key mediator linking maternal stress to innate immune programming and provide a mechanism by which ELS shapes long-term inflammatory tone. *Ella L. Sommer & Niilo V. Valtakari contributed equally.