FcγRIIIB stimulation promotes β1 integrin activation in human neutrophils

Ortiz-Stern, Alejandro; Rosales, Carlos

doi:10.1189/jlb.0504310

Cited by 32 publications

(30 citation statements)

References 83 publications

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“…Confocal microscopy pictures confirm this rapid internalization. An internalization of Fc␥RIIa was previously suggested on the basis of microscopical techniques (63) and radioactivity measurements (64) but was never quantified as we did in the current study. Furthermore in these two previous studies, Fc␥RIIa was described inside the cell after 10 min (62) or 2 min (63) crosslinking.…”

Section: Discussionmentioning

confidence: 57%

The Ubiquitin Ligase c-Cbl Down-Regulates FcγRIIa Activation in Human Neutrophils

Marois

Vaillancourt²,

Marois³

et al. 2009

The Journal of Immunology

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Little is known about the mechanisms that arrest FcγRIIa signaling in human neutrophils once engaged by immune complexes or opsonized pathogens. In our previous studies, we observed a loss of immunoreactivity of Abs directed against FcγRIIa following its cross-linking. In this study, we report on the mechanisms involved in this event. A stimulated internalization of FcγRIIa leading to the down-regulation of its surface expression was observed by flow cytometry and confocal microscopy. Immunoprecipitation of the receptor showed that FcγRIIa is ubiquitinated after stimulation. MG132 and clasto-lactacystin β-lactone inhibited the loss of immunoreactivity of FcγRIIa, suggesting that this receptor was down-regulated via the proteasomal pathway. The E3 ubiquitin ligase c-Cbl was found to translocate from the cytosol to the plasma membrane following receptor cross-linking. Furthermore, c-Cbl was recruited to the same subset of high-density, detergent-resistant membrane fractions as stimulated FcγRIIa itself. Silencing the expression of c-Cbl by small interfering RNA decreased FcγRIIa ubiquitination and prevented its degradation without affecting the internalisation process. It also prolonged the stimulation of the tyrosine phosphorylation response to the cross-linking of the receptor. We conclude that c-Cbl mediates the ubiquitination of stimulated FcγRIIa and thereby contributes to the termination of FcγRIIa signaling via its proteasomal degradation, thus leading to the down-regulation of neutrophil signalisation and function (phagocytosis) through this receptor.

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Section: Discussionmentioning

confidence: 57%

The Ubiquitin Ligase c-Cbl Down-Regulates FcγRIIa Activation in Human Neutrophils

Marois

Vaillancourt²,

Marois³

et al. 2009

The Journal of Immunology

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“…Because no associated molecules are known for Fc␥RIIIB, it has become difficult to establish a signaling mechanism for this receptor. Despite this, Fc␥RIIIB is clearly capable of inducing several cell responses, including calcium transients (14 -16), actin polymerization (17), activation of integrins (18), and activation of nuclear factors (Ref. 19 and this report).…”

Section: Discussionmentioning

confidence: 99%

“…F(abЈ) 2 fragments of mAb 3G8 were prepared as described (18,24). Briefly, Ab was diluted at 2 mg/ml at pH of 3.5, and pepsin was added at 25 g/ml.…”

Section: Preparation Of F(abј) 2 Fragmentsmentioning

confidence: 99%

“…Fc␥RIIIB (CD16B) is present exclusively on neutrophils and it is a GPI-linked receptor, lacking transmembrane and cytoplasmic domains (12,13). Although signaling molecules associated with Fc␥RIIIB are still unknown, several reports show that Fc␥RIIIB can initiate signaling events leading to calcium transients (14 -16), actin polymerization (17), activation of integrins (18), and NF activation (19).…”

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confidence: 99%

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

García‐García

Nieto-Castañeda

Ruiz-Saldaña

et al. 2009

The Journal of Immunology

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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.

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“…More recently, it was found that FcγRIIA, but not FcγRIIIB could induce an increase in L-selectin expression [76]. Opposite to this, FcγRIIIB, but not FcγRIIA, was able to activate β1 integrins [77]. In addition, when the major cell response of neutrophils, arguably phagocytosis, was examined, FcγRIIA was the predominant FcγR mediating this response.…”

Section: Each Fcγr Initiates Particular Signaling Pathways That Lead mentioning

confidence: 99%

Fc receptors: Cell activators of antibody functions

Rosales¹,

Uribe‐Querol²

2013

ABB

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At the onset of an infection early defense systems, such as complement, get into action. Specialized leukocytes (white blood cells) of the innate immune system, including monocytes, macrophages, and neutrophils also participate as a first line of defense against infections. These early responses are rapid but not very specific and are usually not enough to clear completely many infections. The adaptive immune system is also needed to finish the job against many microorganisms. Antibody molecules, produced during the adaptive immune response, are crucial for preventing recurrent infections. Although, IgG antibodies are essential for controlling infections, these molecules do not directly damage the microorganisms they recognize. Today, it is established that leukocytes of the innate immune system are responsible for the protective effects of these antibodies. IgG molecules bind to their cognate antigens and are in turn recognized by specific receptors (Fcγ receptors) on the membrane of leukocytes. Crosslinking these receptors on the surface of leukocytes leads to activation of several effector cell functions. These effector functions are geared toward the destruction of microbial pathogens and the induction of an inflammatory state that is beneficial during infections. However, in autoimmune diseases, antibodies can direct these effector functions against normal tissues and cause severe tissue damage. In recent years, several factors that can modulate the IgG-FcγR interaction have been elucidated. In this review, we describe the main types of Fcγ receptors, and our current view of how antibody variants interact with these receptors to initiate different cell responses. In addition, new findings on the signaling role of individual Fcγ receptors are also discussed.

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FcγRIIIB stimulation promotes β1 integrin activation in human neutrophils

Cited by 32 publications

References 83 publications

The Ubiquitin Ligase c-Cbl Down-Regulates FcγRIIa Activation in Human Neutrophils

The Ubiquitin Ligase c-Cbl Down-Regulates FcγRIIa Activation in Human Neutrophils

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

Fc receptors: Cell activators of antibody functions

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