Dynamic postnatal tissue adaptation controls functional specification of skin-resident tissue macrophages

Summary: Abstract Body: Resident tissue macrophages (RTMs) represent long-lived and stable tissue macrophage populations of prenatal origin found in almost every organ. RTMs in different tissue niches undergo specialized tissue adaptation important in determining their tissue-specific function. However, the adaptation process and subsequent specification of skin RTMs remain poorly understood. Here, by applying time series of postnatal single-cell transcriptome profiling, we show that dermal RTMs undergo dynamic transcriptional shifts during a defined postnatal period that reflect functional differentiation. We found a distinct dermal macrophage subset that appears early in life and exists throughout adulthood, consistent with the long-lived nature of RTMs. Notably, early postnatal RTMs (EpoRTMs) are gradually replaced by transcriptionally distinct major histocompatibility complex class II (MHCII)-high late postnatal RTMs (LpoRTMs) during the postnatal week 2 and 4. Pathway enrichment analysis distinguishes EpoRTMs as metabolically active and LpoRTMs as immunologically active, indicating that postnatal adaptation governs functional changes in dermal RTMs. Upstream analysis predicts a series of cytokines likely to promote postnatal RTM transition, and induction of MHCII expression in LpoRTMs is in part mediated by interferon-γ. Together, our work highlights the time-dependent tissue adaptation of dermal RTMs, which may contribute to regulating skin homeostasis during different postnatal stages. Taegyun Kim¹, Keiko Sakamoto¹, Paul Kim¹, Keisuke Nagao¹ 1. Dermatology Branch, National Institutes of Health, Bethesda, MD, United States. Innate Immunity, Microbiology, and Microbiome