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¹ Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195
² Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine,Columbia, SC 29208
³ Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195

CORRESPONDENCE Martha K. Cathcart: cathcam{at}ccf.org

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, Ca²⁺-independent phospholipase (iPLA₂β) and cytosolic phospholipase (cPLA₂), and substantiate their in vivo importance. These enzymes are cytoplasmic in unstimulated monocytes. Upon MCP-1 stimulation, iPLA₂β is recruited to the membrane-enriched pseudopod. In contrast, cPLA₂ is recruited to the endoplasmic reticulum. Although iPLA₂β or cPLA₂ antisense oligodeoxyribonucleotide (ODN)–treated monocytes display reduced speed, iPLA₂β also regulates directionality and actin polymerization. iPLA₂β or cPLA₂ antisense ODN–treated adoptively transferred mouse monocytes display a profound defect in migration to the peritoneum in vivo. These converging observations reveal that iPLA₂β and cPLA₂ regulate monocyte migration from different intracellular locations, with iPLA₂β acting as a critical regulator of the cellular compass, and identify them as potential targets for antiinflammatory strategies.

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