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Scavenger receptors (Atypical chemokine receptors) eliminate excess chemokines to maintain a chemokine gradient
To reach their target sites, immune and cancer cells migrate along specific chemokine gradients. For such a chemokine gradient to occur, specialized cell types at one end of the gradient produce and secrete chemokines. At the other end of the gradient, superfluous chemokines must be removed from the environment. This task is performed by cells that express so-called atypical chemokine receptors (ACKR), also called "scavenger receptors", on their surface. While classical receptors trigger cell migration upon binding their chemokines, scavenger receptors are primarily responsible for the elimination of superfluous chemokines.
For example, the atypical chemokine receptor ACKR4 is expressed on endothelial cells lining the inner layer of lymphatic vessels. We have shown that ACKR4 recognizes not only the previously known chemokines CCL19 and CCL21 (the ligands for CCR7) and CCL25, but also CCL20, the chemokine for CCR6-expressing immune cells such as mature B cells, subsets of T cells, and dendritic cells. Thus, using microscopic methods, our group has shown that ACKR4 is transported (internalized) into the cell interior after binding in-house produced fluorescently labeled CCL19, CCL21, as well as CCL20 molecules and thus degrades and eliminates bound chemokine (Video 1). We plan to use these new techniques to further investigate the function of ACKR4 or other atypical chemokine receptors as scavenger receptors, in particular to better decipher their signaling pathways, opening new perspectives for the development of therapeutic options against inflammation or tumor cell metastasis.
Video 1: The atypical receptor ACKR4 is a scavenger receptor for fluorescently labeled human CCL20. HeLa cells were transiently transfected with ACKR4-YPet (green) and stimulated with hCCL20-S6Dy649P1 (red). Uptake of the chemokine by live cells was recorded by confocal microscopy (time-lapse video; duration: 25 minutes after chemokine addition). Bright field combined with red fluorescent channel (hCCL20-S6Dy649P1) to the right. Scale = 50µm.
