Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells.
Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells.
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DOI：
10.1096/fj.201800026rr
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发表时间：
2019-01
期刊：
影响因子：
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通讯作者：
Loudon ASI
中科院分区：
文献类型：
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作者：
Ince LM;Zhang Z;Beesley S;Vonslow RM;Saer BR;Matthews LC;Begley N;Gibbs JE;Ray DW;Loudon ASI
生物钟是免疫功能的关键调节器。我们最近强调了生物钟在小鼠肺部炎症模型中的作用。上皮时钟蛋白BMal1需要调节中性粒细胞的募集，以响应炎症的挑战。BMal1调节糖皮质激素受体(GR)向中性粒细胞趋化因子CXC趋化因子配体5(CXCL5)的募集，提供一种候选机制。我们现在证明，在没有节律性糖皮质激素可用的情况下，肺中性粒细胞增多的时钟控制持续存在。在动态平衡条件下，上皮性GR缺失小鼠肺中促炎症趋化因子的表达增加。然而，支气管上皮中GR的缺失阻止了CXCL5的节律性产生，确定GR是赋予CXCL5昼夜节律控制所必需的。令人惊讶的是，尽管有非节律性的CXCL5反应，节律性肺中性粒细胞仍持续存在，这表明存在额外的昼夜节律控制机制。仅删除髓系细胞中的GR并不能阻止肺中性粒细胞的昼夜节律变化，而且地塞米松治疗后显示中性粒细胞炎症减轻。这些新数据表明，GR需要对某些炎性趋化因子进行昼夜节律控制，但仅凭这一点不足以阻止对吸入内毒素的中性粒细胞炎症的昼夜节律控制，髓系细胞谱系中出现了额外的控制机制。-Ince，L.M.，Zhang，Z.，Beesley，S.，Vonlow，R.M.，Saer，B.R.，Matthews，L.C.，Begley，N.，Gibbs，J.E.，Ray，D.W.，Loudon，A.S.I.肺炎症反应的昼夜变化不依赖于呼吸道上皮细胞中有节奏的糖皮质激素信号。
The circadian clock is a critical regulator of immune function. We recently highlighted a role for the circadian clock in a mouse model of pulmonary inflammation. The epithelial clock protein Bmal1 was required to regulate neutrophil recruitment in response to inflammatory challenge. Bmal1 regulated glucocorticoid receptor (GR) recruitment to the neutrophil chemokine, CXC chemokine ligand 5 (CXCL5), providing a candidate mechanism. We now show that clock control of pulmonary neutrophilia persists without rhythmic glucocorticoid availability. Epithelial GR-null mice had elevated expression of proinflammatory chemokines in the lung under homeostatic conditions. However, deletion of GR in the bronchial epithelium blocked rhythmic CXCL5 production, identifying GR as required to confer circadian control to CXCL5. Surprisingly, rhythmic pulmonary neutrophilia persisted, despite nonrhythmic CXCL5 responses, indicating additional circadian control mechanisms. Deletion of GR in myeloid cells alone did not prevent circadian variation in pulmonary neutrophilia and showed reduced neutrophilic inflammation in response to dexamethasone treatment. These new data show GR is required to confer circadian control to some inflammatory chemokines, but that this alone is insufficient to prevent circadian control of neutrophilic inflammation in response to inhaled LPS, with additional control mechanisms arising in the myeloid cell lineage.—Ince, L. M., Zhang, Z., Beesley, S., Vonslow, R. M., Saer, B. R., Matthews, L. C., Begley, N., Gibbs, J. E., Ray, D. W., Loudon, A. S. I. Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells.