跨组织荟萃分析揭示了巨噬细胞衰老的共享和生态位特异性转录特征

摘要(中文译文)

衰老伴随着各组织广泛的转录重塑，然而衰老如何影响不同类别的组织驻留巨噬细胞尚不清楚。巨噬细胞是高度特化的固有免疫细胞，其特性由局部微环境塑造，提示衰老可能引发共同的和生态位特异性的转录反应。本研究对公开可获取的批量及单细胞RNA测序数据集进行荟萃分析，以表征雄性和雌性小鼠各组织巨噬细胞中与年龄相关的转录变化。我们整理并统一处理了来自雄性和雌性C57BL/6小鼠10个不同组织生态位的33个巨噬细胞转录组数据集，考察转录变化与年龄的关系。比较了不同生态位间差异表达的衰老基因的相似性，通路水平分析揭示了保守的年龄相关特征，包括与抗原呈递、抗氧化反应及铁死亡负调控相关的基因集上调，以及与Wnt、GTP酶和细胞外基质组织信号相关的基因集下调。转录因子活性推断显示，各生态位中AP-1（Fos、Jun）、C/EBPβ、PU.1和Egr1的活性随年龄一致激活。荟萃分析在超过四分之三的分析数据集中确定了593个一致的年龄改变基因，这些基因集中于小GTP酶信号失调。得益于可用的数据集较多，对肺泡巨噬细胞和小胶质细胞的聚焦分析揭示了这些巨噬细胞亚型中随年龄改变性别特异性的转录程序。这些发现表明，巨噬细胞衰老受组织生态位和性别共同塑造，并为理解各组织巨噬细胞衰老的转录组特征提供了框架。

Abstract

Aging is accompanied by widespread transcriptional remodeling across tissues, yet how aging impacts different categories of tissue-resident macrophages is not well understood. Macrophages are highly specialized innate immune cells shaped by their local microenvironments, suggesting that aging may elicit both shared and niche-specific transcriptional responses. Here, we performed a meta-analysis of publicly available bulk and single-cell RNA-seq datasets to characterize age-associated transcriptional changes in murine macrophages across tissues and sexes. We curated and uniformly processed 33 macrophage transcriptomic datasets, derived from 10 distinct tissue niches, in male and female C57BL/6 mice, examining transcriptional changes as a function of age. The similarity of differentially expressed aging genes was compared across niches and pathway-level analysis uncovered conserved age-associated signatures, including upregulation of gene sets related to antigen presentation, antioxidant responses, and negative regulation of ferroptosis, alongside downregulation of gene sets related to Wnt, GTPase, and extracellular matrix organization signaling. Transcription factor activity inference identified consistent age-associated activation of AP-1 (Fos, Jun), C/EBPβ, PU.1, and Egr1 across niches. Meta-analysis defined 593 consistently age-altered genes in > 3/4 of analyzed datasets, converging on dysregulation of small GTPase signaling. Focused analysis of alveolar macrophages and microglia, made possible by the larger number of available datasets, revealed sex-specific transcriptional programs altered with age in these macrophage subtypes. These findings demonstrate that macrophage aging is shaped by both tissue niche and sex and provides a framework for understanding the transcriptomic signatures of macrophage aging across tissues.

如何引用