Targeting inflammatory macrophages with hyaluronan tetrasaccharide: effects on fibroblast collagen degradation and synthesis

作者：Eiko Uno, F. Kim, Mihoko Yoshino, Yasunari Sato, Masao Hashimoto, Kenji Watanabe, Yoichi Mizukami, Jun Muto · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1592751 · 被引用次数：2 · 研究领域：Proteoglycans and glycosaminoglycans research、Fibroblast Growth Factor Research、Cell Adhesion Molecules Research

Hyaluronan (HA) provides moisturizing benefits and exhibits unique biological activities based on its molecular weight. While the anti-inflammatory effects of high-molecular-weight HA have been well studied, the impact of hyaluronan tetrasaccharide (HA4), an ultralow-molecular-weight HA, on the skin immune system is not fully understood. Thus, we investigated how HA4 affects the differentiation of M1 macrophages, which increase during photoaging. As a result, we added HA4 during the M1 macrophage differentiation phase and conducted a gene expression analysis. HA4 partially decreased the transition from M0 to M1 macrophages and reduced the expression of proinflammatory cytokines like IL-6. However, the M2 marker IL-1ra increased, while IL-10 levels remained constant, suggesting that HA4 does not fully polarize macrophages toward the M2 phenotype. Normal human dermal fibroblasts (NHDF) were treated with an M1 macrophage-conditioned medium (M1-CM) and a modified version containing HA4 (M1+HA4-CM). The M1+HA4-CM notably decreased the expression of IL-6 and IL-8, along with the collagen-degrading enzyme MMP1. Collagen synthesis assays showed that HA4 helped restore collagen fiber formation. Moreover, RNA-seq analysis of NHDF treated with the conditioned medium confirmed that M1+HA4-CM amplified the expression of genes related to collagen production while decreasing collagen-degrading enzyme gene expression. Neutralization assays employing a TLR4 antibody suggested that decreasing ...