Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation.
Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation.
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DOI：
10.1038/ncomms7221
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发表时间：
2015-02-10
影响因子：
16.6
通讯作者：
Bruscia, Emanuela M.
中科院分区：
文献类型：
--
作者：
Zhang, Ping-xia;Cheng, Jijun;Zou, Siying;D'Souza, Anthony D.;Koff, Jonathan L.;Lu, Jun;Lee, Patty J.;Krause, Diane S.;Egan, Marie E.;Bruscia, Emanuela M.
在囊性纤维化（CF）患者中，过度炎症是肺破坏和疾病发病率的关键因素。我们之前已经证明，由于支架蛋白CAV 1水平降低以及随后不受控制的TLR 4信号传导，巨噬细胞驱动CF小鼠中对LPS的肺过度炎症反应。在这里，我们表明，在人类和小鼠CF巨噬细胞和小鼠CF肺中，减少的CAV 1和因此增加的TLR 4信号传导是由高microRNA-199 a-5 p水平引起的，这是PI 3 K/AKT依赖性的。microRNA-199 a-5 p的下调或AKT信号传导的增加恢复了CF巨噬细胞中的CAV 1表达并减少了过度炎症。重要的是，FDA批准的药物塞来昔布重建了CF巨噬细胞中的AKT/miR-199 a-5 p/CAV 1轴，并改善了Cftr缺陷小鼠的肺部过度炎症。因此，我们鉴定了AKT/miR-199 a-5 p/CAV 1途径作为先天免疫的调节剂，其在CF巨噬细胞中功能失调，导致肺过度炎症。重要的是，塞来昔布靶向该途径。
In Cystic Fibrosis (CF) patients, hyper-inflammation is a key factor in lung destruction and disease morbidity. We have previously demonstrated that macrophages drive the lung hyper-inflammatory response to LPS in CF mice, due to reduced levels of the scaffold protein CAV1 with subsequent uncontrolled TLR4 signaling. Here we show that reduced CAV1 and, consequently, increased TLR4 signaling, in human and murine CF macrophages and murine CF lungs, is caused by high microRNA-199a-5p levels, which are PI3K/AKT-dependent. Down-regulation of microRNA-199a-5p or increased AKT signaling restores CAV1 expression and reduces hyper-inflammation in CF macrophages. Importantly, the FDA approved drug celecoxib reestablishes the AKT/miR-199a-5p/CAV1 axis in CF macrophages, and ameliorates lung hyper-inflammation in Cftr-deficient mice. Thus, we identify the AKT/miR-199a-5p/CAV1 pathway as a regulator of innate immunity, which is dysfunctional in CF macrophages contributing to lung hyper-inflammation. Importantly, this pathway is targeted by celecoxib.
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