Rationale: Systemic sclerosis (SSc) is a chronic and incurable autoimmune disease with high mortality rates, and skin fibrosis is one of distinguishing hallmarks in the pathogenesis. However, macrophage heterogeneity regulating skin fibrosis remain largely unknown./nMethods: We established mouse disease model and performed single-cell RNA-sequencing (scRNA-seq) to resolve the dynamic and heterogenous characteristics of macrophages in skin fibrosis, and the role of TREM2-dependent macrophages in the pathological process was investigated using knockout mice and intraperitoneal transferring TREM2⁺ macrophages combining with functional assays./nResults: We show that TREM2-expressing macrophages (TREM2⁺ MФs) accumulate in injured skin of mice treated by bleomycin (BLM) and human SSc, and their gene signatures and functional pathways are identified in the course of disease. Genetic ablation of Trem2 in mice globally accelerates and aggravates skin fibrosis, whereas transferring TREM2^hi macrophages improves and alleviates skin fibrosis. Amazingly, we found that disease-associated TREM2⁺ MФs in skin fibrosis exhibit overlapping signatures with fetal skin counterparts in mice and human to maintain skin homeostasis, but each has merits in skin remodeling and development respectively./nConclusion: This study identifies that TREM2 acts as a functional molecule and a major signaling by which macrophage subpopulations play a protective role against fibrosis, and disease-associated TREM2⁺ MФs in skin fibrosis might undergo a fetal-like reprogramming similar to fetal skin counterparts.

中文翻译：

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动态病理分析揭示TREM2依赖性巨噬细胞对皮肤纤维化的保护作用

理由：系统性硬化症（SSc）是一种慢性且无法治愈的自身免疫性疾病，死亡率很高，皮肤纤维化是其发病机制的显着特征之一。然而，调节皮肤纤维化的巨噬细胞异质性仍然很大程度上未知。/n方法：我们建立小鼠疾病模型并进行单细胞RNA测序（scRNA-seq）以解析巨噬细胞在皮肤纤维化中的动态和异质性特征，以及巨噬细胞在皮肤纤维化中的作用。使用基因敲除小鼠和腹腔内转移 TREM2 ⁺巨噬细胞并结合功能测定来研究病理过程中 TREM2 依赖性巨噬细胞。/n结果：我们发现表达 TREM2 的巨噬细胞 (TREM2 ⁺ MФs) 在博莱霉素治疗的小鼠损伤皮肤中积聚（ BLM）和人类 SSc，并在疾病过程中确定了它们的基因特征和功能途径。小鼠中Trem2的基因消融会加速和加剧皮肤纤维化，而将 TREM2 转移^到巨噬细胞中会改善和减轻皮肤纤维化。令人惊讶的是，我们发现皮肤纤维化中与疾病相关的 TREM2 ⁺ MФ 与小鼠和人类的胎儿皮肤对应物表现出重叠的特征，以维持皮肤稳态，但各自在皮肤重塑和发育方面都有优点。/n结论：本研究确定 TREM2作为功​​能分子和主要信号传导，巨噬细胞亚群通过其发挥抗纤维化的保护作用，皮肤纤维化中与疾病相关的 TREM2 ⁺ MФ 可能会经历类似于胎儿皮肤对应物的胎儿样重编程。