Macrophage phenotype is determinant for fibrosis development in keloid disease.

Keloid refers to a fibroproliferative disorder characterized by an accumulation of extracellular matrix (ECM) components at the dermis level, overgrowth beyond initial wound, and formation of tumor-like nodule areas. Treating keloid is still an unmet clinical need and the lack of an efficient therapy is clearly related to limited knowledge about keloid etiology, despite the growing interest of the scientific community in this pathology. In past decades, keloids were often studied in vitro through the sole prism of fibroblasts considered as the major effector of ECM deposition. Nevertheless, development of keloids results from cross-interactions of keloid fibroblasts (KFs) and their surrounding microenvironment, including immune cells such as macrophages. Our study aimed to evaluate the effect of M1 and M2 monocyte-derived macrophages on KFs in vitro. We focused on the effects of the macrophage secretome on fibrosis-related criteria in KFs, including proliferation, migration, differentiation, and ECM synthesis. First, we demonstrated that M2-like macrophages enhanced the fibrogenic profile of KFs in culture. Then, we surprisingly founded that M1-like macrophages can have an anti-fibrogenic effect on KFs, even in a pro-fibrotic environment. These results demonstrate, for the first time, that M1 and M2 macrophage subsets differentially impact the fibrotic fate of KFs in vitro, and suggest that restoring the M1/M2 balance to favor M1 in keloids could be an efficient therapeutic lever to prevent or treat keloid fibrosis.