Circulating inflammatory cytokines alter transcriptional activity within fibrotic tissue of Dupuytren's disease patients.
Circulating inflammatory cytokines alter transcriptional activity within fibrotic tissue of Dupuytren's disease patients.
复制标题
循环炎性细胞因子改变掌腱膜挛缩症患者纤维化组织内的转录活性。
DOI：
10.1002/jor.25059
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Tomlinson,RyanE
中科院分区：
文献类型：
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作者：
Wang,MarkL;Rajpar,Ibtesam;Ruggiero,NicholasA;Fertala,Jolanta;Steplewski,Andrzej;Beredjiklian,PedroK;Rivlin,MichaelR;Chen,Yong;Feldman,GeorgeJ;Fertala,Andrzej;Tomlinson,RyanE
迪皮特伦氏病是一种良性的手部纤维增生性疾病，导致手指挛缩，损害功能，降低生活质量。这种疾病的发病率与慢性炎症状态相关，但炎性细胞因子与Dupuytren病之间的任何直接联系尚不清楚。我们假设晚期纤维增生与循环中炎性细胞因子水平升高有关。术前从严重挛缩患者和对照患者中采集血液和纤维化脐带组织。使用多重免疫测定法评价已知炎性细胞因子的血浆浓度。通过RNA测序和免疫组织化学分析来自脐带组织的蛋白质。此外，使用傅里叶变换红外光谱分析富含胶原蛋白的脐带。结果表明，与对照组相比，患者表现出显著升高的循环炎性细胞因子，包括肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-2和IL-12 p70。同样，与对照组相比，在Dupuytren病中检测到IL-4和IL-13的频率显著更高。RNA测序显示5311个差异表达基因和疾病和对照样品之间的明显聚类。除了与纤维增生相关的基因表达增加外，我们还观察到炎症细胞因子激活的转录物上调，包括催乳素诱导蛋白和角蛋白中间丝。通过免疫组织化学在纤维化脊髓组织中检测到IL-2，但未检测到TNF-α。最后，光谱分析显示Dupuytren病组织内胶原含量显著减少和胶原交联改变。总的来说，我们的研究结果表明，严重的Dupuytren病患者表现出显著升高的循环炎性细胞因子，可能会驱动纤维增生。临床意义：本研究的结果为特异性细胞因子谱奠定了基础，该细胞因子谱可能对Dupuytren病的诊断测试和治疗干预有用。
Dupuytren's disease is a benign fibroproliferative disorder of the hand that results in disabling digital contractures that impair function and diminish the quality of life. The incidence of this disease has been correlated with chronic inflammatory states, but any direct association between inflammatory cytokines and Dupuytren's disease is not known. We hypothesized that advanced fibroproliferation is associated with increased levels of circulating inflammatory cytokines. Blood and fibrotic cord tissue were collected preoperatively from patients with severe contracture and control patients. Blood plasma concentrations of known inflammatory cytokines were evaluated using a multiplex immunoassay. Proteins from the cord tissue were analyzed by RNA sequencing and immunohistochemistry. Moreover, collagen‐rich cords were analyzed using Fourier‐transform infrared spectroscopy. The results indicate that patients exhibited significantly elevated circulating inflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐2, and IL‐12p70, as compared with controls. Similarly, IL‐4 and IL‐13 were detected significantly more frequently in Dupuytren's disease as compared with control. RNA sequencing revealed 5311 differentially expressed genes and distinct clustering between diseased and control samples. In addition to increased expression of genes associated with fibroproliferation, we also observed upregulation of transcripts activated by inflammatory cytokines, including prolactin inducible protein and keratin intermediate filaments. IL‐2, but not TNF‐α, was detected in fibrotic cord tissue by immunohistochemistry. Finally, spectroscopic assays revealed a significant reduction of the collagen content and alterations of collagen cross‐linking within the Dupuytren's disease tissues. In total, our results illustrate that patients with severe Dupuytren's disease exhibit substantially elevated circulating inflammatory cytokines that may drive fibroproliferation. Clinical Significance: The results from this study establish the basis for a specific cytokine profile that may be useful for diagnostic testing and therapeutic intervention in Dupuytren's disease.