ARD:上皮HIF2α表达诱导肠屏障功能障碍和关节炎恶化

2022-08-09 MedSci原创 MedSci原创

HIF2α-密蛋白-15通路对于关节炎发作时肠道屏障功能的破坏至关重要,突出了肠道稳态与关节炎之间的功能联系。恢复或保护肠道屏障功能的干预措施,例如 HIF 阻断剂,可用于治疗性地抑制关节炎的发作。

目的:肠道炎症和关节炎密切相关,但迄今为止解释这两个器官相互作用的机制研究很少。考虑到肠道上皮细胞的代谢变化影响其屏障功能,研究肠道粘膜屏障如何影响关节炎的发展。

方法在实验性关节炎和人类类风湿性关节炎(RA)之前、发病时和期间评估肠道缺氧诱导因子(HIF)-2α的表达水平。产生肠上皮细胞特异性HIF2α条件性敲除小鼠(HIF2αΔIEC) 并采用胶原诱导的关节炎模型。记录关节炎的临床和组织学过程;在肠道和次级淋巴器官中分析了T细胞和B细胞亚群;在HIF2αΔIEC和同窝对照小鼠中对肠上皮细胞进行分子 mRNA测序。通过染色质免疫沉淀和荧光素酶实验探索了肠道 HIF2α靶基因。此外,药理学 HIF2α抑制剂PT2977用于抑制关节炎。

结果肠道HIF2α表达在实验性关节炎和RA发作时达到峰值。肠道上皮细胞特异性的HIF2α缺失可抑制关节炎,并与改善肠道屏障功能和减少肠道和淋巴Th1Th17活化有关。从机制上讲,HIF2α诱导了成孔密蛋白(CLDN)-15的转录,从而抑制了肠道屏障的完整性。此外,用HIF2α抑制剂治疗可降低上皮细胞中密蛋白-15的表达并抑制关节炎。

结论这些发现表明,HIF2α-密蛋白-15通路对于关节炎发作时肠道屏障功能的破坏至关重要,突出了肠道稳态与关节炎之间的功能联系。恢复或保护肠道屏障功能的干预措施,例如 HIF 阻断剂,可用于治疗性地抑制关节炎的发作

 

出处:Wen J, Lyu P, Stolzer I, et al. Epithelial HIF2α expression induces intestinal barrier dysfunction and exacerbation of arthritis. Annals of the Rheumatic Diseases 2022;81:1119-1130.

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    2022-08-08 lmm397
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    2022-08-08 wrj0126

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