The transcription factor XBP-1 is essential for the development and survival of dendritic cells
The transcription factor XBP-1 is essential for the development and survival of dendritic cells
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DOI：
10.1084/jem.20070525
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发表时间：
2007-10-01
影响因子：
15.3
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
--
作者：
Iwakoshi, Neal N.;Pypaert, Marc;Glimcher, Laurie H.
树突状细胞(DC)在免疫应答的启动、维持和分解中起着关键作用。DC的存活受到细胞外刺激如细胞因子和Toll样受体(TLR)信号的严格控制，但将这些细胞外刺激转化为DC的生死的细胞内事件仍然知之甚少。内质网(ER)应激，或未折叠蛋白反应(UPR)，是当未折叠蛋白在内质网积累时被激活的信号通路。UPR最保守的臂涉及IRE1α，一种ER跨膜激酶和内切核酸酶，激活转录因子XBP-1来维持ER动态平衡，防止持续ER应激引起的细胞死亡途径的激活。我们报道XBP-1对DC的发育和生存是必不可少的。缺乏XBP-1的淋巴嵌合体具有常规和浆细胞样树突状细胞的数量减少，在基线和对TLR信号的反应中存活率降低。XBP-1在造血祖细胞中的过表达挽救和促进了DC的发育。值得注意的是，与我们检测的其他细胞类型不同，XBP-1通路在未成熟的DC中被结构性激活。
Dendritic cells ( DCs) play a critical role in the initiation, maintenance, and resolution of an immune response. DC survival is tightly controlled by extracellular stimuli such as cytokines and Toll- like receptor ( TLR) signaling, but the intracellular events that translate such extracellular stimuli into life or death for the DC remain poorly understood. The endoplasmic reticulum ( ER) stress, or unfolded protein response ( UPR), is a signaling pathway that is activated when unfolded proteins accumulate in the ER. The most conserved arm of the UPR involves IRE1 alpha, an ER transmembrane kinase and endoribonuclease that activates the transcription factor XBP- 1 to maintain ER homeostasis and prevent activation of cell death pathways caused by sustained ER stress. We report that XBP- 1 is essential for DC development and survival. Lymphoid chimeras lacking XBP- 1 possessed decreased numbers of both conventional and plasmacytoid DCs with reduced survival both at baseline and in response to TLR signaling. Overexpression of XBP- 1 in hematopoietic progenitors rescued and enhanced DC development. Remarkably, in contrast to other cell types we have examined, the XBP- 1 pathway was constitutively activated in immature DCs.