CCR7 Chemokine Receptor-Inducible Inc-Dpf3 Restrains Dendritic Cell Migration by Inhibiting HIF-1α-Mediated Glycolysis
CCR7 Chemokine Receptor-Inducible Inc-Dpf3 Restrains Dendritic Cell Migration by Inhibiting HIF-1α-Mediated Glycolysis
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DOI：
10.1016/j.immuni.2019.01.021
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发表时间：
2019-03-19
期刊：
影响因子：
32.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Liu, Juan;Zhang, Xiaomin;Cao, Xuetao
CCR 7趋化因子受体刺激诱导快速但短暂的树突状细胞（DC）向引流淋巴结迁移，这对于启动保护性免疫和维持免疫稳态至关重要。终止CCR 7介导的DC迁移的机制仍不完全清楚。在这里，我们已经确定了一个长的非编码RNA Inc-Dpf 3，其反馈抑制CCR 7介导的DC迁移。CCR 7刺激通过去除N6-甲基腺苷（m（6）A）修饰来上调Inc-Dpf 3，以防止RNA降解。DC特异性Inc-Dpf 3缺陷增加CCR 7介导的DC迁移，导致过度的适应性免疫应答和炎性损伤。从机制上讲，CCR 7刺激激活了DC中的HIF-1 α转录因子途径，导致代谢重编程朝向糖酵解，以促进DC迁移。Inc-Dpf 3直接与HIF-1 α结合并抑制糖酵解基因Ldha的HIF-1 α依赖性转录，从而抑制DC糖酵解代谢和迁移能力。我们证明了CCR 7诱导的Inc-Dpf 3在将表观遗传和代谢途径偶联到反馈控制DC迁移和炎症反应中的关键作用。
CCR7 chemokine receptor stimulation induces rapid but transient dendritic cell (DC) migration toward draining lymph nodes, which is critical for the initiation of protective immunity and maintenance of immune homeostasis. The mechanisms for terminating CCR7-mediated DC migration remain incompletely understood. Here we have identified a long non-coding RNA Inc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation up-regulated Inc-Dpf3 via removing N6-methyladenosine (m(6)A) modification to prevent RNA degradation. DC-specific Inc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1 alpha transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. Inc-Dpf3 directly bound to HIF-1 alpha and suppressed HIF-1 alpha-dependent transcription of the glycolytic gene Ldha, thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible Inc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.