iPLA2β: front and center in human monocyte chemotaxis to MCP-1

Abstract

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 (cPLA2α), 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, cPLA2α is recruited to the endoplasmic reticulum. Although iPLA2β or cPLA2α antisense oligodeoxyribonucleotide (ODN)–treated monocytes display reduced speed, iPLA2β also regulates directionality and actin polymerization. iPLA2β or cPLA2α 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 cPLA2α 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.

Calcium-Independent Phospholipase A2β-Akt Signaling Is Involved in Lipopolysaccharide-Induced NADPH Oxidase 1 Expression and Foam Cell Formation

“…Like the other sPLA 2 or cPLA 2 families, the iPLA 2 family provides intracellular second messengers by producing arachidonic acid (AA) and lysophospholipids through the hydrolysis of phospholipids. However, iPLA 2 has a specific function different from sPLA 2 or cPLA 2 , which includes chemotaxis to MCP-1 (37,38), control of apoptosis and macrophage adhesion (39,40), and endothelial cell S-phase progression (41). Among the iPLA 2 family members, iPLA 2 ␤ was first recognized and has been the best characterized.…”

Polarization of Macrophages toward M2 Phenotype Is Favored by Reduction in iPLA2β (Group VIA Phospholipase A2)

“…Lysophospholipids (24) generated by PLA 2 s (e.g. lysophosphatidic acid (LPA)) are implicated in monocyte survival and migration (25)(26)(27).…”

Analysis of Two Major Intracellular Phospholipases A2 (PLA2) in Mast Cells Reveals Crucial Contribution of Cytosolic PLA2α, Not Ca2+-independent PLA2β, to Lipid Mobilization in Proximal Mast Cells and Distal Fibroblasts

“…Dissociation of iPLA 2 ␤ from phospholipid remodeling has also been demonstrated recently in testis, macrophages, and pancreatic ␤-cells (44, 76, 77), in which the enzyme appears to play signaling roles in processes such as Ca 2ϩ entry, lipid mediator synthesis, cell migration, exocytosis, and apoptosis (41)(42)(43)(44)(45)(46)(47)(48)(49). However, in BMMCs, iPLA 2 ␤ is apparently nonessential for stimulus-coupled AA mobilization and subsequent eicosanoid generation, granule exocytosis, cytokine secretion, and even upstream Ca 2ϩ entry (Figs.…”

“…Mast cells also express iPLA 2 ␤, a prototypic iPLA 2 isoform, and the iPLA 2 inhibitor bromoenol lactone (BEL) can attenuate granule exocytosis by mast cells (39), leading to the suggestion that iPLA 2 ␤ participates in the regulation of mast cell activation. Although iPLA 2 ␤ has long been thought to play a role in phospholipid remodeling (40), recent studies using mice or cells that are devoid of iPLA 2 ␤ as a result of gene targeting or siRNA knockdown have defined its roles in various signaling events, such as Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel opening (41), lipid mediator generation (42,43), exocytosis (44), cytokine secretion (45), cell migration (46), vascular contractility (47), apoptosis (48,49), cancer (50), and neuronal degeneration (51,52). Because of its roles in Ca 2ϩ gating and lipid mediator generation, the sequential action of iPLA 2 ␤ and cPLA 2 ␣ for the full operation of AA release has been proposed in vascular cells (42).…”