An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.
An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.
复制标题
作者：
昼夜节律系统是免疫功能的重要调节者.人类炎症性肺病经常表现出症状严重程度和肺功能的时间变化，但这些影响的机制和细胞类型仍不清楚。我们发现，肺抗菌反应是由上皮俱乐部（克拉拉）细胞内的昼夜节律钟调制。这些通过趋化因子CXCL5驱动昼夜中性粒细胞向肺募集。在细支气管细胞中时钟基因Bmal1（也称为Arnt1或MOP3）的基因消融破坏了节律性Cxc15表达，导致对脂多糖和细菌感染的过度炎症反应。肾上腺切除术阻断了节律性炎症反应和CXCL5的昼夜节律调节，表明肾上腺轴在驱动CXCL5表达和肺中性粒细胞募集中起关键作用。在Cxcl5位点的糖皮质激素受体占有显示昼夜节律振荡，但这在细支气管特异性消融Bmal1的小鼠中被破坏，导致增强的CXCL5表达，尽管正常的皮质类固醇分泌。在时钟基因破坏的小鼠中，合成的糖皮质激素地塞米松失去抗炎功效。我们现在定义了一种调节机制，将生物钟和糖皮质激素联系起来，以控制一天中的时间变化以及肺部炎症的程度和对细菌感染的反应。
The circadian system is as an important regulator of immune function. Human inflammatory lung diseases frequently show time-of-day variation in symptom severity and lung function, but the mechanisms and cell types that are underlying these effects remain unclear. We show that pulmonary antibacterial responses are modulated by a circadian clock within epithelial club (Clara) cells. These drive circadian neutrophil recruitment to the lung via the chemokine CXCL5. Genetic ablation of the clock gene Bmal1 (also called Arntl or MOP3) in bronchiolar cells disrupts rhythmic Cxcl5 expression, resulting in exaggerated inflammatory responses to lipopolysaccharide and bacterial infection. Adrenalectomy blocks rhythmic inflammatory responses and the circadian regulation of CXCL5, suggesting a key role for the adrenal axis in driving CXCL5 expression and pulmonary neutrophil recruitment. Glucocorticoid receptor occupancy at the Cxcl5 locus shows circadian oscillations, but this is disrupted in mice with bronchiole-specific ablation of Bmal1, leading to enhanced CXCL5 expression despite normal corticosteroid secretion. In clock-gene disrupted mice the synthetic glucocorticoid dexamethasone loses anti-inflammatory efficacy. We now define a regulatory mechanism that links the circadian clock and glucocorticoid hormones to control both time-of-day variation and also the magnitude of pulmonary inflammation and responses to bacterial infection.
登录
查看更多内容
影响因子：
3.1
作者：
Kadioglu, A;Gingles, NA;Andrew, PW
通讯作者：
Andrew, PW
影响因子：
4.8
作者：
Hwang, Jae-Woong;Sundar, Isaac K.;Rahman, Irfan
通讯作者：
Rahman, Irfan
影响因子：
15.9
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
通讯作者：
Link, Daniel C.
DOI：
10.1073/pnas.1106750109
发表时间：
2012-01-10
影响因子：
11.1
作者：
Gibbs, Julie E.;Blaikley, John;Loudon, Andrew S. I.
通讯作者：
Loudon, Andrew S. I.
影响因子：
16
作者：
John, Sam;Sabo, Peter J.;Hager, Gordon L.
通讯作者：
Hager, Gordon L.