Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α
Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α
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DOI：
10.4049/jimmunol.1301593
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发表时间：
2014-10-01
影响因子：
4.4
通讯作者：
Lang, Roland
中科院分区：
文献类型：
--
作者：
Schoenen, Hanne;Huber, Alexandra;Lang, Roland
海藻糖-6，6-二霉菌酸酯（TDM），分枝杆菌索因子及其合成类似物海藻糖-6，6-二山嵛酸酯（TDB）与C型凝集素受体巨噬细胞诱导的C型凝集素（Mincle）和Mcl结合，以激活巨噬细胞。在遗传学上，对TDB/TDM的转录应答已被定义为需要FcR γ-Syk-Card 9信号传导。然而，TDB/TDM触发的激酶激活尚未得到很好的研究，并且很大程度上不知道哪些转录调节因子引起炎症基因表达。在这篇文章中，我们报告说，TDB/TDM只引起弱Syk磷酸化在静息巨噬细胞，低基础Mincle表达一致。然而，LPS引发导致MYD 88依赖性Mincle上调，导致增强的TDB/TDM诱导的激酶活化和更快速的炎症基因表达。TLR诱导的Mincle表达部分规避了TDB/TDM反应中对Mcl的需求。为了剖析TDB/TDM的转录反应，我们挖掘微阵列数据，并确定早期生长反应（Egr）家族转录因子作为直接的Mincle靶基因，而Cebpb和Hif 1 α的上调需要新的蛋白质合成。缺乏C/EBP β的巨噬细胞和树突状细胞几乎完全消除了TDB/TDM反应性，但也未能上调Mincle。在Cebpb缺陷细胞中Mincle表达的逆转录病毒拯救恢复了Egr 1的诱导，但不恢复G-CSF的诱导。在用Dectin-1配体Curdlan刺激后也观察到这种C/EBPb依赖性模式。低氧诱导因子1 α（HIF 1 α）的诱导表达也需要C/EBPb。反过来，HIF 1 α不是Mincle表达、激酶激活和Egr 1或Csf 3表达所必需的，但对NO产生有重要贡献。总之，我们确定C/EBPb作为Mincle表达和炎症基因诱导的中心枢纽，而HIF 1 α控制Nos 2表达。C/EBPb还通过MYD 88依赖性Mincle上调将TLR信号与脐带因子反应性联系起来。
Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, and its synthetic analog Trehalose-6,6-dibehenate (TDB) bind to the C-type lectin receptors macrophage-inducible C-type lectin (Mincle) and Mcl to activate macrophages. Genetically, the transcriptional response to TDB/TDM has been defined to require FcR gamma-Syk-Card9 signaling. However, TDB/TDM-triggered kinase activation has not been studied well, and it is largely unknown which transcriptional regulators bring about inflammatory gene expression. In this article, we report that TDB/TDM caused only weak Syk-phosphorylation in resting macrophages, consistent with low basal Mincle expression. However, LPS-priming caused MYD88-dependent upregulation of Mincle, resulting in enhanced TDB/TDM-induced kinase activation and more rapid inflammatory gene expression. TLR-induced Mincle expression partially circumvented the requirement for Mcl in the response to TDB/TDM. To dissect transcriptional responses to TDB/TDM, we mined microarray data and identified early growth response (Egr) family transcription factors as direct Mincle target genes, whereas upregulation of Cebpb and Hif1 alpha required new protein synthesis. Macrophages and dendritic cells lacking C/EBP beta showed nearly complete abrogation of TDB/TDM responsiveness, but also failed to upregulate Mincle. Retroviral rescue of Mincle expression in Cebpb-deficient cells restored induction of Egr1, but not of G-CSF. This pattern of C/EBPb dependence was also observed after stimulation with the Dectin-1 ligand Curdlan. Inducible expression of hypoxia-inducible factor 1 alpha (HIF1 alpha) also required C/EBPb. In turn, HIF1 alpha was not required for Mincle expression, kinase activation, and Egr1 or Csf3 expression, but critically contributed to NO production. Taken together, we identify C/EBPb as central hub in Mincle expression and inflammatory gene induction, whereas HIF1 alpha controls Nos2 expression. C/EBPb also connects TLR signals to cord factor responsiveness through MYD88-dependent upregulation of Mincle.