Objectives To investigate the pro-phagocytic phenotype of macrophages in SSc and other rheumatic diseases by examining their activation, signaling pathways, and treatment responses, with the goal of uncovering mechanisms that drive enhanced phagocytosis. Methods Single-cell RNA sequencing (scRNA-seq) datasets (GSE138669/GSE212109) from skin and lung macrophages of healthy controls and SSc patients were analyzed. Human monocyte-derived macrophages (hMDM) were differentiated from CD14+ monocytes from healthy controls, SSc, RA, PsA, and axSpA patients. In selected experiments, hMDMs were pretreated with 0.1 μM nintedanib. Phagocytic activity was quantified using pHrodo bioparticles and flow cytometry. Macrophage surface markers were evaluated by flow cytometry, NF-κB signaling by Western blot, and gene expression by RT-qPCR. Results Analysis of scRNA-seq datasets revealed a pro-phagocytic signature in SSc-affected organs. SSc macrophages, particularly the FCGR3A hi cluster in skin, exhibited elevated expression of FCGR genes and enriched FcγR-mediated phagocytosis pathways, accompanied by pro-inflammatory markers. This phenotype extended to FCN1 hi lung macrophages in SSc patients with interstitial lung disease, indicating a systemic pro-inflammatory and phagocytic profile. hMDMs from SSc, RA, and PsA patients demonstrated enhanced phagocytic activity in vitro. Elevated FcγRI and FcγRII levels were identified as key drivers of increased phagocytic activity and subsequent IL-6-driven inflammation. Nintedanib showed reduction in FcγRI expression, suggesting its potential therapeutic benefit in attenuating the phagocytic process. Conclusion This study highlights FcγR-expressing macrophages as drivers of phagocytosis and inflammatory responses in SSc. Dysregulated activation of these macrophages could lead to persistent inflammation and fibrosis in rheumatic diseases, highlighting new potential therapeutic approaches.

中文翻译：

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Fcy 受体表达升高增强了系统性硬化症和相关风湿性疾病中的促炎巨噬细胞吞噬作用


目的 通过检查巨噬细胞的激活、信号通路和治疗反应，研究 SSc 和其他风湿性疾病中巨噬细胞的促吞噬表型，以揭示驱动增强吞噬作用的机制。方法 分析健康对照和 SSc 患者皮肤和肺巨噬细胞的单细胞 RNA 测序 （scRNA-seq） 数据集 （GSE138669/GSE212109）。人单核细胞衍生的巨噬细胞 （hMDM） 与健康对照、SSc 、 RA 、 PsA 和 axSpA 患者的 CD14 + 单核细胞分化。在选定的实验中，用 0.1 μM 尼达尼布预处理 hMDM。使用 pHrodo 生物颗粒和流式细胞术定量吞噬活性。通过流式细胞术评估巨噬细胞表面标志物，通过 Western blot 评估 NF-κB 信号传导，通过 RT-qPCR 评估基因表达。结果 scRNA-seq 数据集的分析揭示了 SSc 受影响器官的促吞噬特征。SSc 巨噬细胞，尤其是皮肤中的 FCGR3A hi 簇，表现出 FCGR 基因表达升高和富集 FcγR 介导的吞噬作用途径，并伴有促炎标志物。这种表型延伸到间质性肺病 SSc 患者的 FCN1 高肺巨噬细胞，表明全身性促炎和吞噬特征。来自 SSc 、 RA 和 PsA 患者的 hMDM 在体外表现出增强的吞噬活性。升高的 FcγRI 和 FcγRII 水平被确定为吞噬活性增加和随后 IL-6 驱动的炎症的关键驱动因素。Nintedanib 显示 FcγRI 表达降低，表明其在减弱吞噬过程方面具有潜在的治疗益处。结论 本研究强调表达 FcγR 的巨噬细胞是 SSc 吞噬作用和炎症反应的驱动因素。 这些巨噬细胞的激活失调可能导致风湿性疾病的持续炎症和纤维化，突出了新的潜在治疗方法。