Department of Pediatrics, University of California, San Diego, La Jolla, CA.
Rady Children's Hospital, San Diego, CA.
J Immunol. 2022 Apr 15;208(8):1947-1959. doi: 10.4049/jimmunol.2101192. Epub 2022 Mar 30.
Immaturity of alveolar macrophages (AMs) around birth contributes to the susceptibility of newborns to lung disease. However, the molecular features differentiating neonatal and mature, adult AMs are poorly understood. In this study, we identify the unique transcriptomes and enhancer landscapes of neonatal and adult AMs in mice. Although the core AM signature was similar, murine adult AMs expressed higher levels of genes involved in lipid metabolism, whereas neonatal AMs expressed a largely proinflammatory gene profile. Open enhancer regions identified by an assay for transposase-accessible chromatin followed by high-throughput sequencing (ATAC-seq) contained motifs for nuclear receptors, MITF, and STAT in adult AMs and AP-1 and NF-κB in neonatal AMs. Intranasal LPS activated a similar innate immune response in both neonatal and adult mice, with higher basal expression of inflammatory genes in neonates. The lung microenvironment drove many of the distinguishing gene expression and open chromatin characteristics of neonatal and adult AMs. Neonatal mouse AMs retained high expression of some proinflammatory genes, suggesting that the differences in neonatal AMs result from both inherent cell properties and environmental influences.
出生时肺泡巨噬细胞（AMs）的不成熟导致新生儿易患肺部疾病。然而，区分新生儿和成熟、成年 AM 的分子特征尚未得到很好的理解。在这项研究中，我们鉴定了小鼠中新生和成年 AM 的独特转录组和增强子景观。尽管核心 AM 特征相似，但成年小鼠 AM 表达更高水平的参与脂质代谢的基因，而新生儿 AM 表达以促炎基因为主的基因谱。通过转座酶可及染色质的测定（ATAC-seq）鉴定的开放增强子区域包含成年 AM 中的核受体、MITF 和 STAT 以及新生儿 AM 中的 AP-1 和 NF-κB 的基序。鼻内 LPS 激活了新生和成年小鼠相似的先天免疫反应，新生鼠中炎症基因的基础表达更高。肺部微环境驱动了新生和成年 AM 的许多区分基因表达和开放染色质特征。新生鼠 AM 保留了一些促炎基因的高表达，这表明新生儿 AM 的差异既源于固有细胞特性，也源于环境影响。
