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β₂-整合素控制人类中性粒细胞中的HIF1α激活

Lovis Kling^1,2, Claudia Eulenberg-Gustavus¹, Uwe Jerke¹

¹Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Berlin, Germany.

Frontiers in immunology

|October 29, 2024

概括

中性粒细胞向炎症部位的迁移涉及β2-整合素,这些β2-整合素控制HIF-1α稳定,并延迟亡. 这种机制确保HIF-1α激活,特别是在炎症部位的中性粒细胞中.

科学领域:

免疫学免疫学免疫学
细胞生物学细胞生物学
分子生物学分子生物学

背景情况:

人类中性粒细胞在低氧和高细胞因子条件下使用β2-整合素迁移到炎症部位.
低氧诱导因子 (HIF) 途径在细胞适应低氧环境方面发挥着至关重要的作用.

研究的目的:

调查酸酶域含酶 (PHDs) 抑制,细胞因子和β2-整合素在中性粒细胞中HIF通路激活中的合作作用.
阐明β2-整合素调节HIF-1α稳定及其对中性粒细胞亡的影响的机制.

主要方法:

利用roxadustat (一种PHD抑制剂) 和normobaric缺氧来诱导伪缺氧和缺氧,分别.
在各种条件下检查HIF-1α蛋白和mRNA水平在附着和悬浮中性粒细胞中,包括炎症介质刺激和β2-整合素阻塞/激活.
研究下游信号通路,包括JAK2-STAT3和翻译启动因子 (eIF4E,4EBP1).
使用纤维素结合试验和药理学HIF-1α抑制评估中性粒细胞亡.

主要成果:

在伪缺氧和缺氧条件下,HIF-1α蛋白在附着中性粒细胞中积累,具有GM-CSF等炎症调解者的添加剂/协同效应.
HIF-1α稳定依赖于β2-整合素,无论是在附着中性粒细胞中,还是在悬浮中性粒细胞中激活时.
通过eIF4E和4EBP1的酸化,以β2-整合素为媒介的HIF-1αmRNA转化,这一过程对于蛋白质上调是必要的,但不够的.
在低血清条件下,HIF-1α稳定延迟了附着中性粒细胞的亡,这种效应通过药理学HIF-1α抑制而逆转.

结论:

在人类中性粒细胞中确定了一种新的β2-整合素依赖的HIF-1α稳定机制.
这种机制限制了HIF-1α激活到向炎症部位迁移的中性粒细胞,将整合素参与与缺氧反应联系起来.
这些发现强调了HIF途径在炎症微环境中对中性粒细胞存活的重要性.

关键词:

粘附性粘附性粘附性粘附性缺氧缺氧是指缺氧的情况.缺氧诱导的因素可能导致缺氧.这是一种炎症炎症炎症炎症.整合物是一种整合物.单细胞 (Monocytes) 是一种单细胞.骨髓状细胞是骨髓状细胞的组成部分.中性粒细胞中性粒细胞.

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