Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9 + TREM2 + macrophages that express SPP1 , GPNMB , FABP5 , and CD63 . In both human and murine hepatic and pulmonary fibrosis, these macrophages were enriched at the outside edges of scarring and adjacent to activated mesenchymal cells. Neutrophils expressing MMP9, which participates in the activation of TGF-β1, and the type 3 cytokines GM-CSF and IL-17A coclustered with these macrophages. In vitro, GM-CSF, IL-17A, and TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers. Such differentiated cells could degrade collagen IV but not collagen I and promote TGF-β1–induced collagen I deposition by activated mesenchymal cells. In murine models blocking GM-CSF, IL-17A or TGF-β1 reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis. Our work identifies a highly specific macrophage population to which we assign a profibrotic role across species and tissues. It further provides a strategy for unbiased discovery, triage, and preclinical validation of therapeutic targets based on this fibrogenic macrophage population.

中文翻译：

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3 型炎症诱导的广泛纤维化巨噬细胞亚群的鉴定

巨噬细胞是组织对损伤反应的中央协调者，其不同的巨噬细胞激活状态在纤维化进展和消退中起着关键作用。识别人类纤维化组织中发现的关键巨噬细胞群可能会导致新的纤维化治疗方法。在这里，我们使用人类肝脏和肺部单细胞 RNA 测序数据集来识别CD9+TREM2+ 表达的巨噬细胞SPP1,GPNMB,FABP5， 和CD63. 在人类和小鼠的肝和肺纤维化中，这些巨噬细胞在瘢痕形成的外边缘和活化的间充质细胞附近富集。表达参与 TGF-β1 激活的 MMP9 的中性粒细胞以及与这些巨噬细胞共簇的 3 型细胞因子 GM-CSF 和 IL-17A。在体外，GM-CSF、IL-17A 和 TGF-β1 驱动人单核细胞分化为表达疤痕相关标记物的巨噬细胞。这种分化的细胞可以降解胶原蛋白 IV，但不能降解胶原蛋白 I，并通过活化的间充质细胞促进 TGF-β1 诱导的胶原蛋白 I 沉积。在小鼠模型中，阻断 GM-CSF、IL-17A 或 TGF-β1 可减少疤痕相关的巨噬细胞扩张和肝或肺纤维化。我们的工作确定了一个高度特异性的巨噬细胞群，我们赋予其跨物种和组织的促纤维化作用。它进一步提供了一种基于这种纤维化巨噬细胞群的治疗靶标的无偏见发现、分类和临床前验证的策略。