Maternal Stress Triggers Early-Life Eczema via Fetal Mast Cell Reprogramming [scRNAseq]

Prenatal stress (PS) is a repeated exposure to aversive situations during pregnancy, including high emotional strain, and suspected to impact physiological systems in infants. Pediatric eczema develops quickly after birth at flexural sites subjected to continuous mechanical constraints. While epidemiological studies have suggested an association between PS and higher risk of eczema in children, no causative biological link has been identified to date. Here we show that early-onset eczema at birth originates from molecular dysregulations of neuroimmune circuits in utero triggered by fluctuations in the maternal hypothalamic-pituitary-adrenal axis. We found that offspring from stressed pregnant dams have dysregulated Mcpt5+ mast cells and skin-projecting neurons, and quickly develop eczema in response to harmless mechanical frictions. We demonstrate that PS transiently modulates maternal corticosterone levels, which profoundly alters the developmental program of skin mast cells expressing Nr3c1 and adjacent sensory neurons conveying mechanosensation. Therapeutic normalization of corticosterone levels or genetic depletion of Mcpt5+ mast cells during stressed gestation prevents dysregulation of neuroimmune pathways and fully protects from eczema development at birth. Our findings support a new model in which early-onset pediatric eczema originates from dysregulations in fetal immune and somatosensory systems caused by fluctuations in maternal glucocorticoids induced by stress. Overall design: Pregnant 8- to 10-week-old dams were subject to chronic prenatal stress (PS) from embryonic day (E)13.5 to E18.5. Skin samples were collected from 8-week old (W8) and 24-week old (W24) control (CT) and PS offspring (pool of 3 mice per group), and single-cell RNA sequencing of isolated CD45+ cells was conducted.