Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis
Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis
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DOI：
10.1002/art.41058
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发表时间：
2020-01-01
影响因子：
13.3
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
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作者：
Soare, Alina;Gyoerfi, Hermina A.;Distler, Joerg H. W.
目的二肽基肽酶4(DPP-4)的表达鉴定了一种参与创面愈合过程中瘢痕形成的真皮成纤维细胞系。然而，DDP-4在组织纤维化中的作用尚不清楚。本研究的目的是评估DPP-4作为治疗系统性硬化症(SSC)患者纤维化的潜在靶点。方法采用实时定量聚合酶链式反应、免疫荧光和Western印迹分析DPP-4在皮肤活检组织和真皮成纤维细胞中的表达。DPP-4的活性受西格列汀和维拉格列汀对DPP4的过度表达、基因敲除和药物抑制的调节。分析了DPP4对人真皮成纤维细胞和不同SSC小鼠模型(各6只)的抑制作用。结果SSC患者纤维化皮肤中DPP-4的表达和DPP-4阳性成纤维细胞数量均增加，且呈转化生长因子-β(TGF-β)依赖性。DPP-4阳性的成纤维细胞表达更高水平的肌成纤维细胞标记物和胶原(与健康对照组相比P<；0.001)。DPP4的过表达促进成纤维细胞的激活，而药物抑制或基因失活则通过干扰转化生长因子β诱导的ERK信号转导而减少收缩蛋白的增殖、迁移和表达，以及胶原的释放(P<；0.001与对照组相比)。Dpp4基因敲除小鼠对博莱霉素诱导的皮肤和肺纤维化不那么敏感(P<；0.0001与野生型对照相比)。DPP4抑制剂的治疗促进了接受博莱霉素攻击的小鼠和患有慢性移植物抗宿主病的小鼠的纤维化消退，并改善了Tsk1小鼠的纤维化(每只P<；0.001与未治疗的对照组相比)。这些抗纤维化作用与炎症的减少有关。结论DPP-4表征了一组活化的成纤维细胞群，表明DPP-4调节转化生长因子β诱导的SSC患者纤维化皮肤成纤维细胞的激活。在耐受性良好的剂量下，DPP4的抑制作用具有很强的抗纤维化作用。由于DPP4抑制剂已经在糖尿病的临床上使用，这些结果可能对SSc患者的纤维化治疗具有直接的翻译意义。
Objective Expression of dipeptidylpeptidase 4 (DPP-4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP-4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP-4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Methods Expression of DPP-4 in skin biopsy samples and dermal fibroblasts was analyzed by real-time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP-4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). Results The expression of DPP-4 and the number of DPP-4-positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor beta (TGF beta)-dependent manner. DPP-4-positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGF beta-induced ERK signaling. DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (P < 0.0001 versus wild-type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft-versus-host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. Conclusion DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGF beta-induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well-tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.