M1/M2 Macrophage Skewing is Related to Reduction in Types I, V, and VI Collagens with Aging in Sun-Exposed Human Skin.

Sun-exposed, aged human skin is fragile because of collagen fragmentation and loss. We recently reported that the balance of M1 and M2 macrophages is associated with chronic inflammation and related inflammaging in sun-exposed human skin. In this study, we analyzed its role in the maintenance of collagen matrix formation by performing histological analyses of human facial skin. In addition, RNA sequencing, protein assays, and functional assays revealed the details of the mechanism. The number of M2 macrophages was positively correlated with the abundance of type I collagen, whereas the M1/M2 ratio was negatively correlated with the abundance of type V and VI collagen, which are the essential minor collagens required for collagen assembly in the skin; however, there was no correlation with type III collagen. Furthermore, M2 macrophages induced the expression of the proteins required for the assembly of collagen fibrils, suggesting that the M1/M2 balance controls not only the quantity but also the quality of the collagen matrix. Indeed, M1 macrophages induced abnormal collagen fibrils consisting of types I, V, and VI collagens. Our results demonstrate the relationship between the M1/M2 balance and the dysregulation of collagen homeostasis in photoaged skin and suggest the possible involvement of macrophages in skin photoaging.

IL-34 Downregulation‒Associated M1/M2 Macrophage Imbalance Is Related to Inflammaging in Sun-Exposed Human Skin.

Macrophages can be polarized into two subsets: a proinflammatory (M1) or an anti-inflammatory (M2) phenotype. In this study, we show that an increased M1-to-M2 ratio associated with a decrease in IL-34 induces skin inflammaging. The total number of macrophages in the dermis did not change, but the number of M2 macrophages was significantly decreased. Thus, the M1-to-M2 ratio was significantly increased in sun-exposed aged skin and positively correlated with the percentage of p21+ and p16+ senescent cells in the dermis. The supernatant of M1 macrophages increased the percentages of senescence-associated ß-galactosidase‒positive cells, whereas the supernatant of M2 macrophages decreased the percentages of senescence-associated ß-galactosidase‒positive cells in vitro. Among the mechanisms that could explain the increase in the M1-to-M2 ratio, we found that the number of IL-34+ cells was decreased in aged skin and negatively correlated with the M1-to-M2 ratio. Furthermore, IL-34 induced the expression of CD206 and IL-10, which are M2 macrophage markers, in an in vitro assay. Our results suggest that a reduction in epidermal IL-34 in aged skin may skew the M1/M2 balance in the dermis and lead to low-grade chronic inflammation and inflammaging.