ABSTRACT
BACKGROUND AND PURPOSE: Induction of cellular migration is the primary effect of chemokine receptor activation. However, several chemokine receptor-like proteins bind chemokines without subsequent induction of intracellular signalling and chemotaxis. It has been suggested that they act as chemokine scavengers, which may control local chemokine levels and contribute to the function of chemokines during inflammation. This has been verified for the chemokine-like receptor proteins D6 and DARC as well as CCX-CKR. Here, we provide evidence for an additional biological function of human (h)CCX-CKR. EXPERIMENTAL APPROACH: We used transfection strategies in HEK293 and human T cells. KEY RESULTS: Co-expression of hCCX-CKR completely inhibits hCXCR3-induced chemotaxis. We found that hCCX-CKR forms complexes with hCXCR3, suggesting a relationship between CCX-CKR heteromerization and inhibition of chemotaxis. Moreover, negative binding cooperativity induced by ligands both for hCXCR3 and hCCX-CKR was observed in cells expressing both receptors. This negative cooperativity may also explain the hCCX-CKR-induced inhibition of chemotaxis. CONCLUSIONS AND IMPLICATIONS: These findings suggest that hCCX-CKR prevents hCXCR3-induced chemotaxis by heteromerization thus representing a novel mechanism of regulation of immune cell migration.
Subject(s)
Chemotaxis, Leukocyte , Down-Regulation , Receptors, CCR/metabolism , Receptors, CXCR3/metabolism , T-Lymphocytes/immunology , Cells, Cultured , Chemokines/metabolism , Fluorescence Resonance Energy Transfer , Gene Expression Regulation , HEK293 Cells , Humans , Immunohistochemistry , Kinetics , Ligands , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Protein Multimerization , Protein Transport , RNA, Messenger , Receptors, CCR/genetics , Receptors, CXCR3/genetics , Recombinant Fusion Proteins/metabolism , Recombinant Proteins/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolismABSTRACT
Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemokines are generally found under both physiological and pathological conditions. Whereas many reports describe chemokine expression in astrocytes and microglia and their role in the migration of leukocytes into the CNS, only few studies describe chemokine expression in neurons. Nevertheless, the expression of neuronal chemokines and the corresponding chemokine receptors in CNS cells under physiological and pathological conditions indicates that neuronal chemokines contribute to CNS cell interaction. In this study, we review recent studies describing neuronal chemokine expression and discuss potential roles of neuronal chemokines in neuron-astrocyte, neuron-microglia, and neuron-neuron interaction.
