Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-β1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.

中文翻译：

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抗 CX3CL1 (fractalkine) 单克隆抗体可减轻硬皮病移植物抗宿主病小鼠模型中的肺和皮肤纤维化

系统性硬化症（SSc）是一种自身免疫性疾病，其特征是血管损伤和炎症，随后导致皮肤和其他内脏器官（包括肺部）过度纤维化。 CX3CL1 (fractalkine) 是一种在内皮细胞上表达的趋化因子，支持表达其特定受体 CX3CR1 的巨噬细胞和 T 细胞迁移到目标组织中。我们之前报道过，抗 CX3CL1 单克隆抗体 (mAb) 治疗可显着抑制转化生长因子 (TGF)-β1 诱导的人真皮成纤维细胞中 I 型胶原和纤连蛋白 1 的表达。此外，抗小鼠 CX3CL1 mAb 可有效抑制博莱霉素和生长因子诱导的 SSc 小鼠模型中的皮肤炎症和纤维化。然而，在启动 CX3CL1 抑制剂治疗人类 SSc 的临床试验之前，需要使用不同的小鼠模型对 SSc 的复杂免疫病理学进行进一步研究。为了评估抗 CX3CL1 mAb 疗法在皮肤和肺纤维化中的临床前效用和功能机制，通过特征性浸润细胞的免疫组织化学染色和 RNA 测序分析，对硬皮病慢性移植物抗宿主病 (Scl-cGVHD) 小鼠模型进行了分析。骨髓移植后第42天，Scl-cGVHD小鼠表现出血清CX3CL1水平升高。腹腔注射抗CX3CL1 mAb抑制了Scl-cGVHD模型皮肤和肺部纤维化的发展，并且没有导致任何明显的不良事件。治疗效果与组织浸润炎症细胞和α-平滑肌肌动蛋白（α-SMA）阳性肌成纤维细胞的数量相关。纤维化皮肤的 RNA 测序分析表明，mAb 治疗显着下调了与巨噬细胞相关炎症和纤维化相关的基因组的 cGVHD 依赖性诱导。在纤维化过程中，mAb 治疗减少了 cGVHD 诱导的皮肤和肺部巨噬细胞和 T 细胞的浸润，尤其是表达 CX3CR1 的巨噬细胞和 T 细胞。结合我们之前在其他 SSc 小鼠模型中的发现，目前的结果表明，抗 CX3CL1 mAb 疗法可能是治疗人类 SSc 和 Scl-cGVHD 等纤维化疾病的合理治疗方法。