NIK prevents the development of hypereosinophilic syndrome-like disease in mice independent of IKKα activation.
NIK prevents the development of hypereosinophilic syndrome-like disease in mice independent of IKKα activation.
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DOI：
10.4049/jimmunol.1200021
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发表时间：
2012-05-01
期刊：
影响因子：
--
通讯作者：
Redecke V
中科院分区：
文献类型：
--
作者：
Häcker H;Chi L;Rehg JE;Redecke V
免疫细胞介导的组织损伤是不同炎症性疾病的共同特征，但其发病机制和涉及的细胞类型差异很大。高嗜酸性粒细胞综合征（HES）是一组炎症性疾病，其特征是外周血和不同器官中致病性嗜酸性粒细胞数量增加。基于临床和实验室的发现，各种形式的HES已经被定义，但驱动嗜酸性粒细胞扩张的分子机制和潜在的信号通路在很大程度上仍然未知。在这里，我们发现丝氨酸/苏氨酸特异性蛋白激酶NF-κB诱导激酶（NIK）缺乏的小鼠在25-30周龄左右发生了一种类似hes的疾病，表现为进行性血液和组织嗜酸性粒细胞增多、组织损伤和过早死亡。与HES的淋巴细胞形式类似，来自NIK缺陷小鼠的CD4+ t细胞表达t辅助2 （Th2）相关细胞因子水平升高，并且通过基因消融CD4+ t细胞可以完全阻止NIK缺陷小鼠的嗜酸性粒细胞增多和存活。然而，基于骨髓嵌合小鼠的实验表明，nik缺陷小鼠的炎症依赖于抗辐射组织，这意味着nik缺陷免疫细胞以非自主的方式介导炎症。令人惊讶的是，疾病的发展独立于IkappaB激酶(IKK)-α激酶的功能，因为携带IKKα激活环突变的小鼠（IKK α被NIK磷酸化）没有发生炎症性疾病。我们的数据表明，NIK在非造血细胞中的活性控制th2细胞的发育，并预防嗜酸性粒细胞驱动的炎症性疾病，最有可能使用独立于已知NIK底物IKKα的信号通路。
Immune cell-mediated tissue injury is the common feature of different inflammatory diseases, yet the pathogenetic mechanisms and cell types involved vary significantly. Hypereosinophilic Syndrome (HES) represents a group of inflammatory diseases that are characterized by increased numbers of pathogenic eosinophilic granulocytes in the peripheral blood and diverse organs. Based on clinical and laboratory findings, various forms of HES have been defined, yet the molecular mechanism and potential signaling pathways that drive eosinophil expansion remain largely unknown. Here we show that mice deficient of the serine/ threonine-specific protein kinase NF-κB inducing kinase (NIK) develop a HES-like disease, reflected by progressive blood and tissue eosinophilia, tissue injury and premature death at around 25–30 weeks of age. Similar to the lymphocytic form of HES, CD4+ T-cells from NIK-deficient mice express increased levels of T-helper 2 (Th2)-associated cytokines, and eosinophilia and survival of NIK deficient mice could completely be prevented by genetic ablation of CD4+ T-cells. Experiments based on bone marrow chimeric mice, however, demonstrated that inflammation in NIK-deficient mice depended on radiation-resistant tissues, implicating that NIK-deficient immune cells mediate inflammation in a non-autonomous manner. Surprisingly, disease development was independent of NIKs known function as IkappaB kinase (IKK)-α kinase, as mice carrying a mutation in the activation loop of IKKα, which is phosphorylated by NIK, did not develop inflammatory disease. Our data show that NIK activity in non-hematopoietic cells controls Th2-cell development and prevents eosinophil-driven inflammatory disease, most likely using a signaling pathway that operates independent of the known NIK substrate IKKα.
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影响因子：
32.4
作者：
Dejardin, E;Droin, NM;Green, DR
通讯作者：
Green, DR
DOI：
10.1073/pnas.0603493103
发表时间：
2006-09-26
影响因子：
11.1
作者：
Andreakos, E.;Williams, R. O.;Feldmann, M.
通讯作者：
Feldmann, M.
影响因子：
10.5
作者：
Li, QT;Lu, QX;Verma, IM
通讯作者：
Verma, IM
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D
影响因子：
30.5
作者：
Claudio, E;Brown, K;Siebenlist, U
通讯作者：
Siebenlist, U