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Human CD206+ Macrophages Show Antifibrotic Effects on Human Fibroblasts via an IL-6-Dependent Mechanism In Vitro.

BACKGROUND
Pathological scarring including keloid and hypertrophic scar causes aesthetic and physical problems, and there are clinical difficulties such as post-treatment recurrence in dealing with pathological scarring. Understanding the mechanisms that underlie scar control in wound healing will help prevent and treat pathological scarring. We focused on CD206+ macrophages in the wound-healing process, and we hypothesized that CD206+ macrophages have antifibrotic effects on fibroblasts.


METHODS
We established a co-culture system for CD206+ macrophages and fibroblasts (cell ratio 1:1). We examined the CD206+ macrophages' antifibrotic effects on fibroblasts after a 72-hr culture, focusing on fibrosis-related genes. To identify key factor(s) in the interaction between CD206+ macrophages and fibroblasts, we analyzed cytokines in a conditioned medium of the co-culture system.


RESULTS
Under co-culture with CD206+ macrophages, the expressions of the following in the fibroblasts were significantly down-regulated: type 1 (fold change, 0.38) and type 3 collagen (0.45), alpha smooth muscle actin (0.24), connective tissue growth factor (0.40), and transforming growth factor-beta (0.66); the expression of matrix metalloproteinase 1 was significantly up-regulated (1.92). Conditioned medium in the co-culture showed a high IL-6 concentration (419 ± 88 pg/mL). When IL-6 was added to fibroblasts, antifibrotic changes in gene expressions (as observed under the co-culture) occurred in the fibroblasts.


CONCLUSIONS
Our in vitro results revealed that CD206+ macrophages have antifibrotic effects on fibroblasts via a paracrine mechanism involving IL-6. Understanding these effects, especially in vivo, will help elucidate the mechanism of scar control in wound healing and contribute to the development of new scar treatments.