Developmental IL7/IL7R signaling in fetal resident tissue macrophages regulates adaptive responses to liver injury

Abstract

Resident tissue macrophages (RTMs) originate from multiple fetal hematopoietic waves and seed organs during the prenatal window where they acquire tissue-specific homeostatic functions. Several growth factors within the fetal niche are required for RTM development, but knowledge of how these signals program tissue-specific RTM survival, identity, and function during the prenatal window is limited. Here, we investigated the functional role of developmental IL7/IL7R signaling on fetal RTM survival and function. IL7 deficiency impaired neonatal RTM establishment, similar to IL7R deficiency, and IL7 was broadly expressed in fetal tissues and co-localized with IL7R+ macrophages. IL7/IL7R signaling regulated cell cycle, apoptotic, and inflammatory transcriptional pathways and activated phospho-AKT signaling in fetal liver myeloid cells. IL7R deletion impaired proliferation of fetal liver monocyte precursors and increased fetal liver macrophage apoptosis. Specific Cre-mediated IL7R deletion in fetal definitive HSC-derived, but not EMP- derived, macrophages caused irrecoverable postnatal loss of IL7R-expressing macrophages in specific tissues, including the liver, demonstrating a specific temporal requirement for IL7R expression during fetal myelopoiesis. Prenatal IL7R blockade subsequently impaired adaptive responses to chronic fibrotic liver injury in adulthood, associated with increased monocyte infiltration and upregulation of pro-inflammatory signaling pathways. These findings redefine IL7 as a developmental myeloid niche factor and demonstrate that IL7/IL7R signaling is co-opted during fetal development to imprint durable RTM programs that shape postnatal tissue immunity and adaptive responses to injury.