Arachidonic acid acts as an intracellular activator of NADPH-oxidase in Fc gamma receptor-mediated superoxide generation in macrophages.

We have previously shown that in neutrophils classical transmembrane signaling consisting of increased [Ca2+]i and hydrolysis of phospholipids was not essential for phagocytosis mediated by more than one receptor (yeast‐IgG, yeast‐C3b/bi, yeast‐Con A). This work deals with the role of this transmembrane signaling in phagocytosis of erythrocyte (E) IgG, which is mediated only by receptors for IgG (FcγRs). The ingestion of E‐IgG was associated with an increase in [Ca+]i and production of inositol phosphates, phosphatidic acid, diacylglycerol, and arachidonic acid, via activation of phospholipases G, D and A2. Related to the same number of particles ingested, the respiratory burst and the transmembrane signaling during phagocytosis of E‐IgG were much smaller than during phagocytosis of yeast‐IgG. In Ca2+‐depleted neutrophils, where the increase in [Ca2+]i and hydrolysis of phospholipids were lacking, the phagocytosis of E‐IgG was depressed by about 60%; the respiratory burst was also depressed due to the decrease of ingestion and of stimulation of NADPH oxidase by residual phagocytosis. Pertussis toxin (PT) did not inhibit the phagocytosis of E‐ IgG but depressed by about 40% the stimulation of li‐ pidic transmembrane signaling and the respiratory burst in normal neutrophils. In Ca2+‐depleted neutrophils the toxin was without effect on ingestion and respiratory burst. Staurosporine did not inhibit the ingestion of E‐ IgG in normal and Ca2+‐depleted neutrophils but depressed by 30‐40% the respiratory burst in normal and not in Ca2+‐depleted neutrophils. Genistein, an inhibitor of tyrosine kinase, did not inhibit the ingestion of E‐IgG but depressed by 30‐40% the respiratory burst both in normal and Ca2+‐depleted neutrophils. These results demonstrate the following findings in human neutrophils. (1) Contrary to the phagocytosis mediated by more than one receptor (yeast‐IgG, yeast‐Con A, yeast‐C3b/bi), the transmembrane signaling involving increase in [Ca2+]i and hydrolysis of phospholipids plays a role in the phagocytosis and respiratory burst mediated by FcγRs alone. Thus, different signal transduction pathways can be involved in phagocytosis and associated respiratory burst depending on the receptor or combination of receptors activated. (2) FcγRs alone promote phagocytosis with two signaling pathways independent of and dependent on [Ca2+]i changes and phospholipid hydrolysis and insensitive to PT, staurosporine, and genistein. (3) The signaling pathways promoting phagocytosis triggered by FcγRs alone are in some way, or at some step, different from those that activate the respiratory burst.

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Immunoglobulin G-mediated phagocytosis activates a calcium-independent, phosphatidylethanolamine-specific phospholipase

Lennartz

Lefkowith

Bromley

et al. 1993

Journal of Leukocyte Biology

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Inhibition of arachidonate release down-regulates immunoglobulin G-mediated phagocytosis. This arachidonate requirement is selective for IgG-opsonized targets, suggesting that arachidonate may act as a second messenger for Fc gamma receptor-mediated phagocytosis. Here we report the characterization of a phospholipase, activated during phagocytosis, that releases arachidonate from phosphatidylethanolamine in the absence of intracellular calcium ([Ca]i < or = 2 nM). In vitro, a phospholipase with these characteristics was detected in soluble and particulate fractions of human monocyte homogenates. (E)-6-(Bromomethylene)tetrahydro-3-(1-naphthalenyl)2H-pyran-2-one, a drug that selectively inhibits Ca-independent phospholipase A2s, is shown to inhibit IgG-mediated phagocytosis and its associated arachidonate release in intact monocytes as well as the in vitro enzyme activity. These findings provide a link between the whole-cell and in vitro data and present the initial characterization of a receptor-activated, calcium-independent phospholipase from human monocytes.

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Arachidonic acid acts as an intracellular activator of NADPH-oxidase in Fc gamma receptor-mediated superoxide generation in macrophages.

Cited by 86 publications

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Phagocytosis: Early Events in Particle Recognition and Uptake

Phagocytosis: Early Events in Particle Recognition and Uptake

Transmembrane signaling pathways involved in phagocytosis and associated activation of NADPH oxidase mediated by FcγRs in human neutrophils

Immunoglobulin G-mediated phagocytosis activates a calcium-independent, phosphatidylethanolamine-specific phospholipase

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