Leukotriene B4 Augments and Restores FcγRs-dependent Phagocytosis in Macrophages

Abstract

Phagocytosis by macrophages is essential for host defense, i.e. preventing invasion of pathogens and foreign materials. (6), and the Rho family proteins (Rho (7) and Rac and Cdc42 (8 -10)) are all required for Fc␥Rs-dependent phagocytosis. LTB 4 is a classical lipid chemoattractant derived from arachidonic acid by the actions of 5-lipoxygenase, 5-lipoxygenase-activating protein (FLAP), and LTA 4 hydrolase. LTB 4 attracts neutrophils and eosinophils by the binding to the LTB 4 -specific G-protein-coupled receptor, BLT1. BLT1, originally identified in our laboratory (11), is expressed in a variety of immune cells, including dendritic cells (12), differentiated T cells (13,14), and mast cells (15). Analysis of BLT1-deficient mice revealed the importance in macrophage biology, as atherogenesis was markedly attenuated in BLT1-deficient mice in an apolipoprotein E (apoE)-null background (16). However, although LTB 4 has been shown to activate macrophage phagocytosis, details of the intracellular mechanism of LTB 4 -dependent activation of phagocytosis remain to be elucidated. Recently, Serezani et al. (17) showed that Fc␥RI engagement results in tyrosine phosphorylation of BLT1 by Src and subsequent formation of a molecular complex of Fc␥RI and BLT1 within lipid rafts that drives phagocytic functions in rat alveolar macrophages. However, it remains to be determined whether there is direct cross-talk between LTB 4 -BLT1 and IgG-Fc␥Rs signaling pathways.In this study, we investigated the function of BLT1 in macrophage phagocytosis using BLT1-deficient mice. BLT1 was necessary for Fc␥R-dependent macrophage

Leukotrienes Target F-actin/Cofilin-1 to Enhance Alveolar Macrophage Anti-fungal Activity

“…Balestrieri et al (67) identified no defect in phagocytosis of the yeast cell wall product zymosan in LTC 4 synthase-deficient peritoneal macrophages. In addition, Okamoto et al (68) have shown that BLT1 Ϫ/Ϫ bone marrow-derived macrophages exhibit lower phagocytic capability of IgG-opsonized zymosan but not of non-opsonized zymosan. Although our work focused on AMs, we did observe a similar dependence on 5-LO products for phagocytosis by peritoneal macrophages.…”

Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

“…The binding models of the activator 23a and the inhibitor 23d in the linoleic acid bound as well as the arachidonic acid bound h-5-LOX active site were made based on the recently published crystal structure of h-5-LOX (PDB code 3V99) [50]. The model of h-5-LOX was further refined using the related PDB structures 3V98 and 3V92 to model Ile673 and its carboxylic acid of the C-terminal (missing in 3V99), which coordinates the catalytic iron in the active site.…”

Targeting leukotriene B4in inflammation

“…The potential pharmacological effects of 5-LO inhibitors have been explored in various disease models applied to 5-LO-deficient mice. These animals are strongly resistant to the lethal effects of shock induced by platelet activating factor (PAF) [85], and more susceptible to infections with Klebsiella pneumoniae, in line with the role of leukotrienes, and in particular LTB 4 , in neutrophil recruitment and phagocytosis [11][12][13] as well as in antimicrobial host defense [14,16,86]. Moreover, 5-LO-deficient mice demonstrated the involvement of this pathway in respiratory [87,88] and cardiovascular [45,49,50,89,90] disorders.…”

“…In this context, it has been shown that LTB 4 exerts a modulatory effect on innate immune cells, driving and controlling the defense mechanisms of this system against bacteria and viruses. For example, LTB 4 stimulates phagocytes to increase the microbial phagocytosis and killing [11][12][13] and enhances the expression of antimicrobial defense [14][15][16][17]. Moreover, LTB 4 impacts the adaptive immunity and regulates the trafficking of B-and T-cells from the lymphoid compartment into peripheral tissues as well as the T-cell responses during the infections [18][19][20][21][22][23][24].…”