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* Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas,
Laboratorio de Medicina Experimental, and
Servicio de Immunologia, Hospital Gregorio Marañón, Madrid, Spain; and
Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a Gi-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of Gi and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving Gi and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
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