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 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 . 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 , 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.

中文翻译：

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巨噬细胞表型是瘢痕疙瘩疾病纤维化发展的决定因素

瘢痕疙瘩是指一种纤维增生性疾病，其特征是细胞外基质（ECM）成分在真皮水平累积、超出初始伤口过度生长以及肿瘤样结节区域的形成。尽管科学界对这种病理学的兴趣日益浓厚，但治疗疤痕疙瘩仍然是一个未得到满足的临床需求，并且缺乏有效的治疗方法显然与对疤痕疙瘩病因学的了解有限有关。在过去的几十年里，人们经常通过成纤维细胞的唯一棱镜来研究疤痕疙瘩，成纤维细胞被认为是 ECM 沉积的主要效应器。然而，疤痕疙瘩的形成是疤痕疙瘩成纤维细胞（KF）与其周围微环境（包括巨噬细胞等免疫细胞）交叉相互作用的结果。我们的研究旨在评估 M1 和 M2 单核细胞来源的巨噬细胞对 KF 的影响。我们重点研究巨噬细胞分泌组对 KF 中纤维化相关标准的影响，包括增殖、迁移、分化和 ECM 合成。首先，我们证明 M2 样巨噬细胞增强了培养物中 KF 的纤维化特征。然后，我们令人惊讶地发现，即使在促纤维化环境中，M1 样巨噬细胞也可以对 KF 具有抗纤维化作用。这些结果首次证明，M1 和 M2 巨噬细胞亚群对 KF 的纤维化命运有不同的影响，并表明恢复 M1/M2 平衡以有利于疤痕疙瘩中的 M1 可能是预防或治疗疤痕疙瘩纤维化的有效治疗手段。