Inhibition of SDF-1 receptors CXCR4 and CXCR7 attenuates acute pulmonary inflammation via the adenosine A(2B)-receptor on blood cells.
Inhibition of SDF-1 receptors CXCR4 and CXCR7 attenuates acute pulmonary inflammation via the adenosine A(2B)-receptor on blood cells.
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DOI：
10.1038/cddis.2016.482
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发表时间：
2017-05-25
影响因子：
9
通讯作者：
Reutershan J
中科院分区：
文献类型：
--
作者：
Konrad FM;Meichssner N;Bury A;Ngamsri KC;Reutershan J
急性肺部炎症的特征是多形核中性粒细胞迁移到肺的不同区室中。最近的研究表明，趋化因子基质细胞衍生因子 (SDF)-1 及其受体 CXCR4 和 CXCR7 影响免疫细胞的迁移，其活性与腺苷浓度相关。我们研究了 CXCR4 和 CXCR7 抑制的特殊作用以及与腺苷 A2B 受体的潜在联系，腺苷 A2B 受体在肺部发挥重要的抗炎作用。吸入 LPS 45 分钟后，给予 CXCR4 抑制剂 (AMD3100) 减少了跨内皮和跨上皮迁移，而 CXCR7 拮抗作用仅影响上皮迁移。在 A2B−/− 小鼠中，任何一种药物均未检测到抗炎作用。使用嵌合小鼠，我们发现造血细胞上的 A2B 对于 CXCR4/7 抑制的抗炎作用至关重要。两种抑制剂均降低野生型小鼠支气管肺泡灌洗液中 TNFα、IL6、CXCL1 和 CXCL2/3 的水平，同时不影响 A2B−/− 小鼠中趋化因子的释放。炎症增强了这两种受体的表达，并且抑制它们会增加炎症时 A2B 的水平。人上皮/内皮的体外测定证实了我们的体内研究结果。在炎症过程中，抑制 CXCR4 和 CXCR7 受体可防止野生型小鼠的微血管通透性，但在 A2B−/− 小鼠中则不然，这凸显了活性 A2B 受体在这种情况下的关键作用。两种抑制剂的组合在防止毛细血管渗漏方面具有协同作用。总之，我们确定了 CXCR4 和 CXCR7 抑制在急性肺部炎症中的关键作用，这取决于 A2B 受体信号传导。
Acute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils into the different compartments of the lung. Recent studies showed evidence that the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 influence migration of immune cells and their activity was linked to adenosine concentrations. We investigated the particular role of CXCR4- and CXCR7-inhibition and the potential link to the adenosine A2B-receptor, which plays an important anti-inflammatory role in the lung. After LPS-inhalation for 45 minutes, administration of the CXCR4-inhibitor (AMD3100) decreased transendothelial and transepithelial migration, whereas CXCR7-antagonism influenced epithelial migration exclusively. In A2B−/− mice, no anti-inflammatory effects were detectible through either one of the agents. Using chimeric mice, we identified A2B on hematopoietic cells to be crucial for these anti-inflammatory effects of CXCR4/7-inhibition. Both inhibitors decreased TNFα, IL6, CXCL1 and CXCL2/3 levels in the bronchoalveolar lavage of wild type mice, while not influencing the chemokine release in A2B−/− mice. Inflammation augmented the expression of both receptors and their inhibition increased A2B-levels upon inflammation. In vitro assays with human epithelium/endothelium confirmed our in vivo findings. During inflammation, inhibition of CXCR4- and CXCR7-receptors prevented microvascular permeability in wild type but not in A2B−/− mice, highlighting the pivotal role of an active A2B-receptor in this setting. The combination of both inhibitors had a synergistic effect in preventing capillary leakage. In conclusion, we determined the pivotal role of CXCR4- and CXCR7-inhibition in acute pulmonary inflammation, which depended on A2B-receptor signalling.
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影响因子：
6.5
作者：
Asai, Jun;Takenaka, Hideya;Kishimoto, Saburo
通讯作者：
Kishimoto, Saburo
DOI：
10.4049/jimmunol.1401957
发表时间：
2015-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hoegl S;Brodsky KS;Blackburn MR;Karmouty-Quintana H;Zwissler B;Eltzschig HK
通讯作者：
Eltzschig HK
影响因子：
8
作者：
Konrad, F. M.;Knausberg, U.;Reutershan, J.
通讯作者：
Reutershan, J.
影响因子：
82.9
作者：
Ceradini, DJ;Kulkarni, AR;Gurtner, GC
通讯作者：
Gurtner, GC
影响因子：
4.8
作者：
Konrad, Franziska M.;Neudeck, Gianna;Reutershan, Joerg
通讯作者：
Reutershan, Joerg