The Chemokine Receptor CCR7 Uses Distinct Signaling Modules With Biased Functionality to Regulate Dendritic Cells.

José Luis Rodríguez-Fernández,Olga Criado-García

doi:10.3389/fimmu.2020.00528

Abstract

Chemotaxis is a molecular mechanism that confers leukocytes the ability to detect gradients of chemoattractants. Chemokine receptors are well-known regulators of chemotaxis in leukocytes; however, they can regulate several other activities in these cells. This information has been often neglected, probably due to the paramount role of chemotaxis in the immune system and in biology. Therefore, the experimental data available on the mechanisms used by chemokine receptors to regulate other functions of leukocytes is sparse. The results obtained in the study of the chemokine receptor CCR7 in dendritic cells (DCs) provide interesting information on this issue. CCR7 guides the DCs from the peripheral tissues to the lymph nodes, where these cells control T cell activation. CCR7 can regulate DC chemotaxis, survival, migratory speed, cytoarchitecture, and endocytosis. Biochemical and functional analyses show: first, that CCR7 uses in DCs the PI3K/Akt pathway to control survival, the MAPK pathway to control chemotaxis, and the RhoA pathways to regulate actin dynamics, which in turn controls migratory speed, cytoarchitecture, and endocytosis; second, that these three signaling pathways behave as modules with a high degree of independence; and third, that although each one of these routes can regulate several functions in different settings, CCR7 promotes in DCs a functional bias in each pathway. The data uncover an interesting mechanism used by CCR7 to regulate the DCs, entailing multifunctional signaling pathways organized in modules with biased functionality. A similar mechanism could be used by other chemoattractant receptors to regulate the functions of leukocytes.

Highlights

Chemokine receptors regulate chemotaxis, a process that allows cells to detect gradients of chemoattractants
When CCR7 was stimulated in the mature DCs (maDCs) that were in serum-free medium, it was observed that the pro-apoptotic signaling described above was turned off because this receptor induced the activation of the signaling axis PI3K/Akt (9, 10, 12, 19, 38, 39) which, as shown below, is a core component of a pro-survival pathway in these cells (Figure 1)
Our studies indicate that the CCR7-induced stimulation of migratory speed, endocytosis, and changes in cytoarchitecture in maDCs is mediated by the RhoA pathway (11, 13)

Summary

Introduction

A process that allows cells to detect gradients of chemoattractants. When CCR7 was stimulated in the maDCs that were in serum-free medium, it was observed that the pro-apoptotic signaling described above was turned off because this receptor induced the activation of the signaling axis PI3K/Akt (9, 10, 12, 19, 38, 39) which, as shown below, is a core component of a pro-survival pathway in these cells (Figure 1). These results suggest that the PI3K/Akt pathway constitute a signaling module that largely controls CCR7-induced survival, but no other CCR7-mediated functions in maDCs (see below).

Results

Conclusion