Characterization of human dermal macrophages in the context of aging

Macrophages are the most abundant immune cell population in the human dermis. They are critical regulators of tissue homeostasis and regeneration and play an important role in pathogen defense. Each tissue has a unique macrophage population with a tissue-specific phenotype that is shaped by the tissue environment. Skin aging is accompanied by reduced regenerative capacity and chronic low-grade inflammation. Macrophages are suggested to contribute to this imbalance of pro- and anti-inflammatory molecules, the inflammaging process. Alterations in macrophage number and phenotype have not yet been described for human skin. Therefore, the aim of this thesis was to study dermal macrophages in the context of skin aging to reveal the role of macrophages in age-dependent disorders of the skin.

In this study, scRNA-seq and immunohistochemistry analysis demonstrated that macrophage numbers increased in human aged skin. Analysis of differentially expressed genes between young and aged skin macrophages revealed a more pro-inflammatory M1 phenotype of dermal macrophages in aged skin with high resemblances to skin MDMs. This led to the suggestion that MDMs replace and supplement skin-resident macrophages over time. In contrast, in vitro aged MDMs had an impaired ability to differentiate to the M1 phenotype. Using co-culture experiments with aged dermal fibroblast, it was demonstrated, that the aged microenvironment polarizes the macrophages to a more pro-inflammatory phenotype in the skin. This emphasizes the role of the aged microenvironment on the development of altered macrophage phenotype in aged skin tissue. Pro-inflammatory M1 MDMs in turn impacted the fibroblast phenotype in its metabolic age, ECM remodeling and inflammatory state. Thus, the accumulation of pro-inflammatory M1 found in aged human skin tissue could contribute to alterations of aged skin phenotype and the development of skin disorders. 



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