CCR7 Chemokine Receptor-Inducible Inc-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 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.