Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells

• Published in: Blood 2004-08, Vol.104 (3), p.619-625
• Main Authors: Sánchez-Sánchez, Noelia, Riol-Blanco, Lorena, de la Rosa, Gonzalo, Puig-Kröger, Amaya, García-Bordas, Julio, Martín, Daniel, Longo, Natividad, Cuadrado, Antonio, Cabañas, Carlos, Corbí, Angel L., Sánchez-Mateos, Paloma, Rodríguez-Fernández, José Luis
• Format: Article
• Language: English
• Subjects: Apoptosis - physiology; Biological and medical sciences; Cell Differentiation - drug effects; Cell Survival; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - physiology; Dendritic Cells - ultrastructure; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Humans; Immunobiology; Microscopy, Electron, Scanning; Modulation of the immune response (stimulation, suppression); NF-kappa B - physiology; Pertussis Toxin - pharmacology; Receptors, CCR7; Receptors, Chemokine - physiology; Recombinant Proteins; Signal Transduction - physiology; Transfection
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-11-3943

Acquisition of CCR7 expression is an important phenotype change during dendritic cell (DC) maturation that endows these cells with the capability to migrate to lymph nodes. We have analyzed the possible role of CCR7 on the regulation of the survival of DCs. Stimulation with CCR7 ligands CCL19 and CCL21 inhibits apoptotic hallmarks of serum-deprived DCs, including membrane phosphatidylserine exposure, loss of mitochondria membrane potential, increased membrane blebs, and nuclear changes. Both chemokines induced a rapid activation of phosphatidylinositol 3′-kinase/Akt1 (PI3K/Akt1), with a prolonged and persistent activation of Akt1. Interference with PI3K, Gi, or G protein βγ subunits abrogated the effects of the chemokines on Akt1 activation and on survival. In contrast, inhibition of extracellular signal-related kinase 1/2 (Erk1/2), p38, or c-Jun N-terminal kinase (JNK) was ineffective. Nuclear factor–κB (NFκB) was involved in the antiapoptotic effects of chemokines because inhibition of NFκB blunted the effects of CCL19 and CCL21 on survival. Furthermore, chemokines induced down-regulation of the NFκB inhibitor IκB, an increase of NFκB DNA-binding capability, and translocation of the NFκB subunit p65 to the nucleus. In summary, in addition to its well-established role in chemotaxis, we show that CCR7 also induces antiapoptotic signaling in mature DCs.