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CCR7 Chemokine Receptor-Inducible lnc-Dpf3 Restrains Dendritic Cell Migration by Inhibiting HIF-1α-Mediated Glycolysis
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...
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Published in: | Immunity (Cambridge, Mass.) Mass.), 2019-03, Vol.50 (3), p.600-615.e15 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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 lnc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation upregulated lnc-Dpf3 via removing N6-methyladenosine (m6A) modification to prevent RNA degradation. DC-specific lnc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1α transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. lnc-Dpf3 directly bound to HIF-1α and suppressed HIF-1α-dependent transcription of the glycolytic gene Ldha, thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible lnc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.
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•lnc-Dpf3 feedback restrains CCR7-induced DC migration and inflammatory response•CCR7 stimulation upregulates lnc-Dpf3 via m6A demethylation to prevent its degradation•lnc-Dpf3 suppresses DC migration via inhibiting HIF1α-dependent glycolysis•lnc-Dpf3 directly binds to HIF1α and inhibits HIF1α activity via an HRE motif
CCR7-mediated DC migration needs to be suppressed in a timely manner to avoid aberrant inflammatory responses. Liu and colleagues demonstrate that feedback of a long non-coding RNA lnc-Dpf3 restrains CCR7-mediated DC migration via directly inhibiting HIF-1α-dependent glycolysis. |
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ISSN: | 1074-7613 1097-4180 |
DOI: | 10.1016/j.immuni.2019.01.021 |