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 β-galactosidase‒positive cells, whereas the supernatant of M2 macrophages decreased the percentages of senescence-associated β-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.