Leukotriene B₄ augments and restores FcγRs-dependent phagocytosis in macrophages

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 B₄ (LTB₄) is a classical lipid chemoattractant derived from arachidonic acid. Leukotriene B₄ receptor 1 (BLT1), a high affinity LTB₄ receptor, is expressed in a variety of immune cells such as neutrophils, macrophages, and dendritic cells. Although LTB₄ 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 LTB₄-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 LTB₄-BLT1 signaling plays a pivotal role in macrophage phagocytosis and innate immunity.