Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis.
Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis.
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DOI：
10.1016/j.immuni.2013.07.018
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发表时间：
2013-08-22
期刊：
影响因子：
32.4
通讯作者：
Wirtz S
中科院分区：
文献类型：
--
作者：
McHedlidze T;Waldner M;Zopf S;Walker J;Rankin AL;Schuchmann M;Voehringer D;McKenzie AN;Neurath MF;Pflanz S;Wirtz S
肝纤维化是慢性肝病的后果，因此是死亡率和发病率的主要原因。临床证据和动物研究表明，由于慢性肝细胞应激的免疫反应，局部组织稳态被扰乱。不明确的应激相关炎症网络被认为介导细胞外基质成分的逐渐积累，最终导致纤维化和肝衰竭。在这里，我们报道了白介素-33 （IL-33）的肝脏表达是体内严重肝纤维化所必需的和充分的。我们已经证明IL-33的促纤维化作用与肝脏固有淋巴样细胞（ILC2）的激活和扩张有关。我们确定了ilc2衍生的IL-13，通过转录因子STAT6和肝星状细胞活化，通过ii型IL-4受体依赖的信号传导起作用，作为il -33依赖的病理组织重塑和纤维化的关键下游细胞因子。我们的数据揭示了与肝纤维化有关的关键免疫网络，并支持了IL-33生物活性调节用于治疗目的的概念。
Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix-components, ultimately leading to fibrosis and liver-failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33’s pro-fibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.
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DOI：
10.1073/pnas.0812690106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Cayrol, Corinne;Girard, Jean-Philippe
通讯作者：
Girard, Jean-Philippe
影响因子：
32.4
作者：
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Li X
影响因子：
14.2
作者：
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通讯作者：
McKenzie, Andrew N. J.
影响因子：
25.7
作者：
Elsharkawy, Ahmed M.;Oakley, Fiona;Lin, Feng;Packham, Graham;Mann, Derek A.;Mann, Jelena
通讯作者：
Mann, Jelena
影响因子：
5.4
作者：
Besnard, Anne-Gaelle;Togbe, Dieudonnee;Ryffel, Bernhard
通讯作者：
Ryffel, Bernhard