Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis
Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis
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DOI：
10.1038/onc.2011.53
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发表时间：
2011-08-01
期刊：
影响因子：
8
通讯作者：
Maru, Y.
中科院分区：
文献类型：
--
作者：
Tomita, T.;Sakurai, Y.;Maru, Y.
我们之前已经证明，在转移前的肺中，原发性肿瘤诱导的两种内源性 Toll 样受体 4 (TLR4) 配体 S100A8 和血清淀粉样蛋白 A3 (SAA3) 的表达产生了肿瘤坏死因子 (TNF)α。然而，人们对信号网络的机制细节以及与肺生理学的相关性知之甚少。在这里，我们将 Clara 细胞识别为网络的控制塔。萘消融 Clara 细胞抑制了 CD11b+ TLR4+ 细胞的肺部募集和自发性肺转移。 Clara 细胞表达 TLR4，SAA3 通过 TLR4 自动扩增。野生型和 TLR4 敲除小鼠之间的相互骨髓移植证明肺 TLR4+ Clara 细胞可以源自骨髓。 SAA3 诱导肺泡 II 型细胞和巨噬细胞中的 TNF α 表达。肺泡 II 型细胞和 Clara 细胞的原代共培养表明，肺泡 II 型细胞中 TNF α 的诱导依赖于 Clara 细胞介导的 SAA3 扩增。细菌内毒素诱导 SAA3 也需要 Clara 细胞和 TLR4。因此，肺转移土壤可能以内毒素微生物持续攻击导致的稳态炎症反应失调为特征。癌基因 (2011) 30, 3429-3439; doi：10.1038/onc.2011.53； 2011 年 3 月 14 日在线发布
We have previously shown that tumor necrosis factor (TNF)alpha produced from primary tumor-induced expression of two endogenous Toll-like receptor 4 (TLR4) ligands, S100A8 and serum amyloid A3 (SAA3), in pre-metastatic lungs. However, mechanistic details of the signaling network and relevance to pulmonary physiology are poorly understood. Here, we identify Clara cells as a control tower of the network. Clara cell ablation by naphthalene suppressed pulmonary recruitment of CD11b+ TLR4+ cells and spontaneous lung metastasis. Clara cells turned out to express TLR4 through which SAA3 was auto-amplified. Reciprocal bone marrow transplantation between wild-type and TLR4 knockout mice demonstrated that pulmonary TLR4+ Clara cells could be derived from bone marrow. SAA3-induced TNF alpha expression in both alveolar type II cells and macrophages. Primary co-cultures of alveolar type II cells and Clara cells revealed that the induction of TNF alpha in alveolar type II cells was dependent on the Clara cell-mediated amplification of SAA3. SAA3 induction by bacterial endotoxin also required both Clara cells and TLR4. Thus, pulmonary metastatic soil may feature deregulation of homeostatic inflammatory responses to constant assaults of microbes with endotoxin. Oncogene (2011) 30, 3429-3439; doi:10.1038/onc.2011.53; published online 14 March 2011