FcγRIIA and FcγRIIIB Mediate Nuclear Factor Activation through Separate Signaling Pathways in Human Neutrophils

Abstract

Receptors for IgG Abs (Fcγ receptors) are capable of triggering diverse cell responses in leukocytes. In neutrophils, two Fcγ receptors, namely FcγRIIA and FcγRIIIB, are constitutively expressed. The signaling pathways that regulate FcγRIIA-mediated phagocytosis have been relatively well described. However, the different signaling pathways that lead to NF activation after engagement of each Fcγ receptor have only been partially described. To address this problem, neutrophils were stimulated by cross-linking selectively each type of Fcγ receptor with specific mAbs, and NF activation was then analyzed. FcγRIIIB, but not FcγRIIA, promoted a robust increase in phosphorylated ERK in the nucleus, and also efficient phosphorylation of the NF Elk-1. Complete mAb 3G8 (anti-FcγRIIIB) induced a higher response than did F(ab′)2 fragments of mAb 3G8, suggesting a possible synergistic effect of both FcγR receptors. However, mAb IV.3 (anti-FcγRIIA) alone did not cause an increase of phosphorylated ERK in the nucleus. FcγRIIIB-induced nuclear phosphorylation of ERK, and of Elk-1, was not affected by Syk, PI3K, or MEK inhibitors. In contrast, FcγRIIA- or FcγRIIIB-mediated phosphorylation of cytoplasmic ERK depended on Syk, PI3K, and MEK. Also, ERK, but not MEK, was constitutively present in the nucleus, and FcγRIIIB cross-linking did not increase the levels of nuclear ERK or MEK. These data clearly show that different neutrophil Fcγ receptors possess different signaling capabilities. FcγRIIIB, but not FcγRIIA, activates a unique signaling pathway leading to the nuclear-restricted phosphorylation of ERK and Elk-1, independently of Syk, PI3K, or MEK.

Inhibition of Erythrocyte Invasion andPlasmodium falciparumMerozoite Surface Protein 1 Processing by Human Immunoglobulin G1 (IgG1) and IgG3 Antibodies

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“…Crosslinking of hFcγRIIA by IgG ICs results in the phosphorylation of ITAM tyrosine residues, followed by recruitment and activation of the tyrosine kinase Syk. This leads to calcium mobilization, activation of MAPK pathways, activation of NF-κB, and inflammatory cell activation (11). Two codominantly expressed alleles of hFcγRIIA differ by an arginine or a histidine at amino acid position 131 and by their affinity for hIgG2.…”

Kawasaki disease and soy: potential role for isoflavone interaction with Fcγ receptors

“…ITAM phosphorylation permits docking of signaling proteins to the receptor molecule, which then initiates a cascade of events promoting inflammatory responses. The type of inflammatory response initiated varies according to the specific FcGR undergoing regulatory phosphorylation (14,15) and whether the ITAM motif resides in the cytoplasmic tail of the FcGR or in an associated protein (24,25). Tyrosine protein kinase also regulates the inhibitory FcGR2B signals via an immunoreceptor tyrosine-based inhibitory (ITIM) motif (Figure 2).…”