Chemotaxis Calcium and Chemotaxis

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

Chemokines are chemoattractant cytokines that act through G protein-coupled receptors (GPCRs) to mediate the directed migration (or chemotaxis) of leukocytes. Chemokine receptors couple to heterotrimeric guanine nucleotide-binding proteins (G proteins) to activate phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC). PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP₂) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP₃), which is critical for leukocyte chemotaxis. PLC- hydrolyzes PIP₂ to produce both inositol 1,4,5-trisphosphate (IP₃), which stimulates intracellular Ca²⁺ mobilization, and diacylglycerol (DAG), which is required for the activity of many isoforms of protein kinase C (PKC). PLC-2 and PLC-3 are not required for the chemotaxis of neutrophils; however, the role of these enzymes in mediating lymphocyte chemotaxis has been unclear. Bach et al. isolated T lymphocytes from wild-type mice and mice deficient in both PLC-2 and PLC-3 (PLC-23 KO mice) and performed chemotaxis assays in which they determined the percentages of cells that migrated in response to the chemokine SDF-1, the ligand for the chemokine receptor CXCR4. The percentage of responding PLC-23 KO T lymphocytes was about half that of the wild-type cells, over a range of concentrations of SDF-1. This was not due to differences in CXCR4 abundance between the PLC-23 KO and wild-type T lymphocytes, as assessed by flow cytometry. Chelation of intracellular Ca²⁺ largely inhibited chemotaxis of wild-type T lymphocytes to SDF-1, whereas pharmacological inhibition of PKC had no such effect. Intracellular Ca²⁺ flux assays demonstrated that SDF-1-induced Ca²⁺ mobilization was severely compromised in PLC-23 KO compared with wild-type T lymphocytes. These data suggest that PLC--mediated intracellular Ca²⁺ mobilization, but not PKC activation, is important for T lymphocyte chemotaxis. Although chemokine receptor-mediated activation of PI3K is critical for the chemotaxis of all leukocyte subsets, the contribution of PLC- isoforms to chemotaxis appears to be cell-specific.

T. L. Bach, Q.-M. Chen, W. T. Kerr, Y. Wang, L. Lian, J. K. Choi, D. Wu, M. G. Kazanietz, G. A. Koretzky, S. Zigmond, C. S. Abrams, Phospholipase C is critical for T cell chemotaxis. J. Immunol. 179, 2223-2227 (2007). [PubMed]