A novel MEK-ERK-AMPK signalling axis controls chemokine receptor CCR7-dependent survival in human mature dendritic cells

14 p.-9 fig.Chemokine receptor CCR7 directs mature dendritic cells (mDCs) to secondary lymph nodes (LNs) where these cells regulate the activation of T cells. CCR7 also promotes survival in mDCs, which is believed to take place largely through Akt-dependent signalling mechanisms. We have analysed the involvement of the AMP-dependent kinase (AMPK) in the control of CCR7-dependent survival. A pro-apoptotic role for AMPK is suggested by the finding that pharmacological activators induce apoptosis, whereas knocking-down of AMPK with siRNA extends mDCs survival. Pharmacological activation of AMPK also induces apoptosis of mDCs in the LNs. Stimulation of CCR7 leads to inhibition of AMPK, through phosphorylation of Ser485, which was mediated by Gi/Gbut not by Akt or S6K, two kinases that control the phosphorylation of AMPK on Ser485 in other settings. Using selective pharmacological inhibitors, we show that CCR7-induced phosphorylation of AMPK on Ser485 is mediated by MEK and ERK. Coimmunoprecipitation analysis and Proximity Ligation Assays (PLA) indicate that AMPK associates with ERK, but not with MEK. The results suggest that in addition to Akt-dependent signalling mechanisms, CCR7 can also promote survival of mDCs through a novel MEK1/2-ERK1/2-AMPK signalling axis. The data also suggest that AMPK may be a potential target to modulate mDC lifespan and the immune response.*This work was supported by grants awarded by Ministerio de Educación y Ciencia (SAF2005- 00801), Ministerio de Ciencia e Innovación (SAF2008-01468), Ministerio de Economía y Competitividad (SAF2011-23890), Ministerio de Economía y Competitividad (SAF2011-23890), RIER (RETICS Program/ Instituto de Salud Carlos III) (RD08/0075) and Consejería de Educación y Empleo from Comunidad de Madrid (Raphyme, S2010/BMD-2350). PLC was supported by a FPI scholarship (Ministerio de Economía y competitividad), CGM was supported by a contract associated to grant Raphyme S2010/BMD-2350 (Consejería de Educación y Empleo. Comunidad de Madrid). LGC and JFB were supported by scholarship FPU and I3P intro, respectively (Ministerio de Educación y Ciencia). JTB and CED were recipients of JAEdoc and I3P contracts (Consejo Superior de Investigaciones Científicas-Fondo Social Europeo). CDM was partially supported fellowship FPI, conferred by the Ministerio de Educación y Ciencia (Spain) and by a contract associated to grant RD08/0075 (RIER).Peer reviewe