Activation of pulmonary invariant NKT cells leads to exacerbation of acute lung injury caused by LPS through local production of IFN-γ and TNF-α by Gr-1+ monocytes
Activation of pulmonary invariant NKT cells leads to exacerbation of acute lung injury caused by LPS through local production of IFN-γ and TNF-α by Gr-1+ monocytes
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DOI：
10.1093/intimm/dxq460
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发表时间：
2011-02-01
影响因子：
4.4
通讯作者：
Kawakami, Kazuyoshi
中科院分区：
文献类型：
--
作者：
Aoyagi, Tetsuji;Yamamoto, Natsuo;Kawakami, Kazuyoshi
不变自然杀伤T（iNKT）细胞已知在多种临床情况下的炎症反应调节中起关键作用。在本研究中，我们评估了iNKT细胞对由气管内给予脂多糖（LPS）引起的急性肺损伤（ALI）发展的作用。缺乏这些细胞的Jα18基因敲除小鼠在肺部发生的中性粒细胞炎症反应程度与对照小鼠相同。接下来，用iNKT细胞激活剂α -半乳糖神经酰胺对小鼠进行气管内致敏，然后用LPS进行激发。在此模型中，小鼠出现严重的肺损伤，并且所有小鼠在LPS注射后72小时内死亡。这些小鼠肺部的干扰素 - γ（IFN - γ）和肿瘤坏死因子（TNF） - α显著升高。在组织病理学分析中，给予抗IFN - γ和TNF - α的中和性单克隆抗体可减轻肺损伤并提高其存活率。流式细胞术分析显示，IFN - γ在自然杀伤（NK）细胞、iNKT细胞以及Gr - 1（暗淡 +）Ly - 6C（+）单核细胞中表达，而TNF - α主要在Gr - 1（明亮 +）Ly - 6G（+）中性粒细胞和Gr - 1（暗淡 +）Ly - 6C（+）单核细胞中检测到。另外，在单独用LPS处理的小鼠中，肺部未检测到IFN - γ，Gr - 1（明亮 +）Ly - 6G（+）中性粒细胞是TNF - α产生的主要细胞来源。抗Gr - 1单克隆抗体可减轻ALI并降低这些细胞因子的水平。这些结果表明，iNKT细胞的激活导致LPS引起的ALI显著加重，并且Gr - 1（+）单核细胞被募集到肺部，表达IFN - γ和TNF - α，并在这些反应的发展中起重要作用。
Invariant NK T (iNKT) cells are known to play a critical role in the regulation of inflammatory responses in various clinical settings. In the present study, we assessed the contribution of iNKT cells to the development of acute lung injury (ALI), which was caused by intra-tracheal administration of LPS. J alpha 18 gene-disrupted mice lacking these cells underwent neutrophilic inflammatory responses in lungs at an equivalent level as control mice. Next, mice were sensitized intra-tracheally with alpha-galactosylceramide, an activator of iNKT cells, followed by challenge with LPS. In this model, mice showed severe lung injury, and all mice were killed within 72 h after LPS injection. IFN-gamma and tumor necrosis factor (TNF)-alpha were strikingly elevated in the lungs of these mice. Administration of neutralizing mAb against IFN-gamma and TNF-alpha attenuated lung injury in a histopathological analysis and improved their survival rate. Flow cytometric analysis revealed that IFN-gamma was expressed in NK cells, iNKT cells and also Gr-1(dull+)Ly-6C(+) monocytes and TNF-alpha was detected mainly in Gr-1(bright+)Ly-6G(+) neutrophils and Gr-1(dull+)Ly-6C(+) monocytes. Otherwise, in mice treated with LPS alone, IFN-gamma was not detected in the lungs and Gr-1(bright+)Ly-6G(+) neutrophil was a main cellular source of TNF-alpha production. Anti-Gr-1 mAb resulted in the attenuation of ALI and decrease in the level of these cytokines. These results indicated that activation of iNKT cells led to striking exacerbation of ALI caused by LPS and that Gr-1(+) monocytes were recruited in the lungs with expressing IFN-gamma and TNF-alpha and played an important role in the development of these responses.