Leukotriene B4 Augments and Restores FcγRs-dependent Phagocytosis in Macrophages

• DOI: 10.1074/jbc.m110.175497
• Publication Date: 2010-10-20T00:20:51Z
• Authors: Fuyuki Okamoto; Kazuko Saeki; Hideki Sumimoto; Sho Yamasaki; Takehiko Yokomizo
• Keywords: 0303 health sciences; Macrophages; Receptors, IgG; Intracellular Signaling Peptides and Proteins; Receptors, Leukotriene B4; GTP-Binding Protein alpha Subunits, Gi-Go; Protein-Tyrosine Kinases; Leukotriene B4; Immunity, Innate; Mice, Mutant Strains; 3. Good health; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Gene Expression Regulation; Phagocytosis; Animals; Syk Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction

Phagocytosis by macrophages is essential for host defense, i.e. preventing invasion of pathogens and foreign materials. Macrophages engulf immunoglobulin G (IgG)-opsonized particles through the action of the receptors for the Fc of IgG (FcγRs). Leukotriene B(4) (LTB(4)) is a classical lipid chemoattractant derived from arachidonic acid. Leukotriene B(4) receptor 1 (BLT1), a high affinity LTB(4) receptor, is expressed in a variety of immune cells such as neutrophils, macrophages, and dendritic cells. Although LTB(4) has been shown to enhance macrophage phagocytosis, few studies have investigated the intracellular mechanisms involved in this in detail. Furthermore, there have been no reports of the direct cross-talk between LTB(4)-BLT1 and IgG-FcγRs signaling. Here, we show that FcγRs-dependent phagocytosis was attenuated in BLT1-deficient macrophages as compared with wild-type (WT) cells. Moreover, cross-talk between LTB(4)-BLT1 and IgG-FcγRs signaling was identified at the level of phosphatidylinositol 3-OH kinase (PI3K) and Rac, downstream of Syk. In addition, the trimeric G(i) protein (G(i)) was found to be essential for BLT1-dependent phagocytosis. Surprisingly, we found that LTB(4)-BLT1 signaling restores phagocytosis in the absence of FcγRs signaling. These data indicate that LTB(4)-BLT1 signaling plays a pivotal role in macrophage phagocytosis and innate immunity.