Stimulation of Human Neutrophils by Chemotactic Factors Is Associated with the Activation of Phosphatidylinositol 3-Kinase γ

Naccache, Paul H.; Levasseur, S.; Lachance, Geneviève; Chakravarti, Sumone; Bourgoin, Sylvain G.; McColl, Shaun R.

doi:10.1074/jbc.m001780200

Cited by 71 publications

(56 citation statements)

References 53 publications

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“…5). Because many studies have shown that PI3K is activated after PMN stimulation (39,53,54), our results suggest that this activation results in the delivery of a negative signal, which counters positive regulatory pathways in the regulation of the rate of PMN migration. Protein tyrosine phosphorylation/dephosphorylation, on the other hand, serves as a downstream signal that most likely occurs after fMLP stimulation and CD47 translocation.…”

Section: Discussionmentioning

confidence: 78%

The Role of CD47 in Neutrophil Transmigration

Liu

Merlin

Burst

et al. 2001

Journal of Biological Chemistry

175

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CD47, a cell surface glycoprotein, plays an important role in modulating neutrophil (PMN) migration across endothelial and epithelial monolayers. Here we show that anti-CD47 monoclonal antibodies (mAbs) delay PMN migration across collagen-coated filters or T84 epithelial monolayers toward the chemoattractant formylmethionylleucylphenylalanine (fMLP). Despite delayed transmigration by anti-CD47 mAbs, the numbers of PMN migrating across in either condition were the same as in the presence of control non-inhibitory mAbs. Cell surface labeling and immunoprecipitation demonstrated upregulation of CD47 to the PMN cell surface with kinetics similar to those of the transmigration response. Subcellular fractionation studies revealed redistribution of CD47 from intracellular compartments that co-sediment with secondary granules to plasma membrane-containing fractions after fMLP stimulation. Experiments performed to investigate potential signaling pathways revealed that inhibition of tyrosine phosphorylation with genistein reversed the anti-CD47-mediated PMN migration delay, whereas inhibition of phosphatidylinositol 3-kinase only partially reversed anti-CD47 effects that correlated with a rapid increase in PMN cell surface CD47. Analysis of the contribution of epithelial-expressed CD47 to PMN transmigration revealed that PMN migration across CD47-deficient epithelial monolayers (CaCO2) was significantly increased after stable transfection with CD47. These results suggest that cell surface CD47 and downstream tyrosine phosphorylation signaling events regulate, in part, the rate of PMN migration during the inflammatory response.

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Section: Discussionmentioning

confidence: 78%

The Role of CD47 in Neutrophil Transmigration

Liu

Merlin

Burst

et al. 2001

Journal of Biological Chemistry

175

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“…Upon binding the chemokine, the activated receptor releases the Gβγ heterodimer from associated trimeric G-proteins, which can then promote the activation of phosphatidylinositol 3-kinase-γ (PI3Kγ), the production of phosphatidylinositol 3,4,5 trisphosphate and the activation of protein kinase B (akt/PKB). Activation of this signaling cascade is thought to play a pivotal role during both human and mouse neutrophil migration by stimulating F-actin polymerization [29][30][31][32]. However, the lack of PI3Kγ in knockout mice does not appear to affect random neutrophil migration, even in the presence of a chemoattractant (e.g.…”

Section: Discussionmentioning

confidence: 99%

Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses

Gaines

Tien

Olins

et al. 2008

Experimental Hematology

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Objective-The capacity of neutrophils to eradicate bacterial infections is dependent on normal development and the activation of functional responses, which include chemotaxis and the generation of oxygen radicals during the respiratory burst. A unique feature of the neutrophil is its highly lobulated nucleus, which is thought to facilitate chemotaxis but may also play a role in other critical neutrophil functions. Nuclear lobulation is dependent on the expression of the inner nuclear envelope protein, the lamin B receptor (LBR), mutations of which cause hypolobulated neutrophil nuclei in human Pelger-Huët anomaly (PHA) and the "ichthyosis" (ic) phenotype in mice. In this study we have investigated roles for LBR in mediating neutrophil development and the activation of multiple neutrophil functions, including chemotaxis and the respiratory burst.Materials and Methods-A progenitor EML cell line was generated from an ic/ic mouse, and derived cells that lacked LBR expression were induced to mature neutrophils and then examined for abnormal morphology and functional responses.Results-Neutrophils derived from EML-ic/ic cells exhibited nuclear hypolobulation identical to that observed in ichthyosis mice. The ic/ic neutrophils also displayed abnormal chemotaxis, supporting the notion that nuclear segmentation augments neutrophil extravasation. Furthermore, promyelocytic forms of ic/ic cells displayed decreased proliferative responses and produced a deficient respiratory burst upon terminal maturation.Conclusions-Our studies of promyelocytes that lack LBR expression have identified roles for LBR in regulating not only the morphologic maturation of the neutrophil nucleus but also proliferative and functional responses that are critical to innate immunity.

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“…Plasma membranes were isolated as previously described (27,28). Briefly, neutrophils (40 ϫ 10 6 cells/ml) were incubated with 1 mM DFP for 30 min at room temperature, washed, and kept for 5 min at 37°C before stimulation with 3 mg/ml MSU crystals.…”

Section: Isolation Of Plasma Membranesmentioning

confidence: 99%

Crystal-Induced Neutrophil Activation: XI. Implication and Novel Roles of Classical Protein Kinase C

Popa-Nita

Proulx

Paré

et al. 2009

The Journal of Immunology

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Monosodium urate (MSU) crystals are among the most potent proinflammatory stimuli, and an innate immune inflammatory response to the crystal surface is involved in the pathology of gouty arthritis. Furthermore, MSU crystals have recently been identified as danger signals able to induce the maturation of dendritic cells. Release of the crystals into the joint cavity promotes an acute inflammation characterized by a massive infiltration of neutrophils that leads to tissue damage. Protein kinase C (PKC) represents a family of serine/threonine kinases that play central signaling roles in multiple cellular responses. This family of kinases is divided into three subfamilies based on second messenger requirements: conventional (or classical), novel, and atypical. Despite their role in signal transduction, very little is known about the involvement of the PKC family in the inflammatory reaction induced by MSU crystals. In the present study, we show that MSU crystals activate conventional PKC isoforms, and that this activation is necessary for the MSU crystal-induced degranulation and generation of a chemotactic activity in the supernatants of MSU crystal-stimulated human neutrophils. Evidence is also obtained that the tyrosine kinase Syk is a substrate of PKC and that the PKC-mediated serine phosphorylation of Syk is necessary to its interaction with the regulatory subunit of PI3K kinases (p85) and thus to the subsequent activation of these lipid kinases. These results suggest novel means of modulating neutrophil responses (through the specific regulation of PKC) during the acute phase of MSU crystal-induced inflammation.

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Stimulation of Human Neutrophils by Chemotactic Factors Is Associated with the Activation of Phosphatidylinositol 3-Kinase γ

Cited by 71 publications

References 53 publications

The Role of CD47 in Neutrophil Transmigration

The Role of CD47 in Neutrophil Transmigration

Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses

Crystal-Induced Neutrophil Activation: XI. Implication and Novel Roles of Classical Protein Kinase C

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