Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis
Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis
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DOI：
10.1136/annrheumdis-2017-212597
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发表时间：
2018-06-01
影响因子：
27.4
通讯作者：
Kollias, George
中科院分区：
文献类型：
--
作者：
Ntari, Lydia;Sakkou, Maria;Kollias, George
目的类风湿性关节炎和脊柱关节炎患者的死亡率较高，主要由心脏合并症引起。ThuTNF（Tg 197）关节炎模型发展肿瘤坏死因子（TNF）驱动的和间充质滑膜成纤维细胞（SF）依赖性多发性关节炎。在这里，我们调查是否这种模式的发展，类似于人类患者，共病心脏病理和探索关节炎心脏comorbidities.Methods的细胞和分子机制，心脏功能进行组织病理学分析和超声心动图评价在Tg 197模型。瓣膜间质细胞（VIC）被携带ColVI-Cre转基因的小鼠靶向。采用Tg 197 ColVI-Cre Tnfr 1（fl/fl）和Tg 197 ColVI-Cre Tnfr 1（cneo/cneo）突变小鼠，探讨间质TNF信号转导在心脏瓣膜病发生发展中的作用。致病性VIC和SFs进行了进一步分析比较RNA测序analysis.Results Tg 197小鼠发展左侧心脏瓣膜疾病，其特征是瓣膜纤维化，炎症的迹象最小。增厚的瓣膜区域几乎完全由过度增殖的表达ColVI的间充质VIC组成。病理学发展导致瓣膜狭窄和左心室功能障碍，伴有心绞痛发作，偶尔发生瓣膜返流。病理学的TNF依赖性通过药理学抑制或间充质特异性遗传消融或TNF/TNFR 1信号传导激活后的疾病调节来指示。Tg 197衍生的VIC表现出离体活化表型，使人想起Tg 197衍生的SF的活化致病表型。SFs和VIC之间的显着功能相似性，揭示了通过RNA-seq分析，表明共同的细胞机制TNF介导的arthritides和心脏comorbidity.Conclusions心脏瓣膜病和慢性多发性关节炎的合并症是有效的建模在Tg 197关节炎模型和共享共同的TNF/TNFR 1介导的，间充质细胞特异性的病因机制。
Objectives Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities.Methods Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying the ColVI-Cretransgene. Tg197 ColVI-Cre Tnfr1(fl/fl) and Tg197 ColVI-Cre Tnfr1(cneo/cneo) mutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis.Results Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative ColVI-expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype ex vivo, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities.Conclusions Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms.