Leukotriene B4 Augments and Restores FcγRs-dependent Phagocytosis in Macrophages

Fuyuki Okamoto,Kazuko Saeki,Hideki Sumimoto,Sho Yamasaki,Takehiko Yokomizo

doi:10.1074/jbc.m110.175497

Fuyuki Okamoto, Kazuko Saeki + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m110.175497

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Abstract

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.

Highlights

Phagocytes play an essential role in recognition of opsonized materials [1, 2]
BLT1 Is Required for Macrophage Phagocytosis via Fc␥Rs— Leukotriene B4 (LTB4) is a known potent chemoattractant for neutrophils, whereas the role of BLT1 in activating macrophages has not been clearly defined
LTB4 Potentiates Fc␥R-dependent Rac Activation—To determine whether the cross-talk between the LTB4-BLT1 and immunoglobulin G (IgG)-Fc␥R signaling pathways resulted in enhanced phagocytosis in macrophages, we examined the activation of Syk induced by incubation with IgG beads and LTB4

Summary

Introduction

Phagocytes play an essential role in recognition of opsonized materials [1, 2]. Binding of IgG-containing immune complexes to Fc␥Rs induces cross-linking of Fc␥Rs and subsequent phosphorylation of tyrosine residues in the immunoreceptor tyrosine-based activation motif (ITAM) of the FcR common ␥-chain (FcR␥) by Src family kinases, such as Lyn and Hck. We identified cross-talk between LTB4-BLT1 and IgG-Fc␥Rs signaling pathways at the level of PI3K and Rac, downstream of Syk. using FcR␥-deficient mice and retroviral gene transfer techniques, we showed that LTB4 stimulation alone is able to induce phagocytosis in macrophages that are deficient in Fc␥Rs signaling.

Results

Conclusion