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Age-related changes in the phenotype and function of mouse skin macrophages

ABSTRACT: Skin ageing is accompanied by chronic low-grade inflammation (“inflammaging”) and progressive remodelling of the dermal extracellular matrix, yet the cellular changes that initiate these processes early in life remain poorly defined. Here we used single-cell RNA sequencing (scRNA-seq) of dorsal skin from young (8-week), middle-aged (26-week) and aged (52-week) male C57BL/6 mice to map age-related shifts in cellular composition, with a focus on macrophages. Whereas the relative proportions of most cell types remained largely stable, the macrophage compartment expanded markedly in the oldest skin. Sub-clustering resolved four macrophage populations, three of which expanded or emerged with age. The Mac4 population, marked by S100a8 and S100a9 and a Cd14-high monocyte-derived signature, was detected only in aged skin and was confirmed in situ by F4/80, S100a8 and S100a9 co-staining. Cell–cell communication analysis predicted increased macrophage-to-fibroblast signalling in aged skin, including the pro-fibrotic mediators Thbs1 and Spp1, accompanied by up-regulation of collagen and fibrosis-associated genes in a subset of fibroblasts (FB3/FB4). Notably, collagen transcripts increased while COL5A3 protein decreased and dermal collagen architecture appeared disorganised by second-harmonic-generation imaging, pointing to post-transcriptional control of matrix remodelling. Ex vivo treatment of aged skin with the secretome of γ-irradiated peripheral blood mononuclear cells (PBMC-sec) reduced the macrophage expansion towards a more youthful composition and down-regulated fibrosis-associated fibroblast genes. Together, these findings identify the early emergence of monocyte-derived, pro-inflammatory and potentially pro-fibrotic macrophage subsets as a feature of mouse skin ageing and suggest that PBMC-sec can partially counteract these changes.

ORGANISM(S): Mus musculus

PROVIDER: GSE336400 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.

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Age-related changes in the phenotype and function of mouse skin macrophages

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