iPLA(2)β: front and center in human monocyte chemotaxis to MCP-1

Monocyte chemoattractant protein-1 (MCP-1) directs migration of blood monocytes to inflamed tissues. Despite the central role of chemotaxis in immune responses, the regulation of chemotaxis by signal transduction pathways and their in vivo significance remain to be thoroughly deciphered. In this study, we examined the intracellular location and functions of two recently identified regulators of chemotaxis, Ca(2+)-independent phospholipase (iPLA(2)β) and cytosolic phospholipase (cPLA(2)α), and substantiate their in vivo importance. These enzymes are cytoplasmic in unstimulated monocytes. Upon MCP-1 stimulation, iPLA(2)β is recruited to the membrane-enriched pseudopod. In contrast, cPLA(2)α is recruited to the endoplasmic reticulum. Although iPLA(2)β or cPLA(2)α antisense oligodeoxyribonucleotide (ODN)–treated monocytes display reduced speed, iPLA(2)β also regulates directionality and actin polymerization. iPLA(2)β or cPLA(2)α antisense ODN–treated adoptively transferred mouse monocytes display a profound defect in migration to the peritoneum in vivo. These converging observations reveal that iPLA(2)β and cPLA(2)α regulate monocyte migration from different intracellular locations, with iPLA(2)β acting as a critical regulator of the cellular compass, and identify them as potential targets for antiinflammatory strategies.