Phosphatidylinositol 3-Kinase Controls Antineutrophil Cytoplasmic Antibodies—Induced Respiratory Burst in Human Neutrophils

Kettritz, Ralph; Choi, Mira; Butt, Waseem; Rane, Madhavi J.; Rolle, Susanne; Luft, Friedrich C.; Klein, Jon B.

doi:10.1097/01.asn.0000019411.36000.06

Cited by 63 publications

(53 citation statements)

References 28 publications

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“…Thus far, no differences in the signaling pathways between PR3-and MPO-specific ANCAs have been revealed. Previously, the findings from a study by Ben-Smith et al and those from our group were able to demonstrate the importance of the PI 3-kinase/Akt pathway in controlling ANCA-induced activation (15,16). Herein we show that PI 3-kinase/Akt is also needed for ANCA-induced activation of GM-CSFprimed neutrophils.…”

Section: Discussionsupporting

confidence: 65%

“…Neutrophils were isolated from the heparinized whole blood of healthy human donors as described previously (16). Cell viability was detected in every cell preparation by trypan blue dye exclusion.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, the central role of neutrophils in the induction of ANCA-mediated vasculitis was shown by neutrophil depletion in a mouse model of glomerulonephritis (12). Investigations of the underlying signal transduction pathways that control this cytokine-mediated priming and ANCA-induced activation of neutrophils identified the participation of p38 MAPK, ERK, protein kinase C, Syk, p21 ras , and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt (9,10,(13)(14)(15)(16).…”

mentioning

confidence: 99%

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Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt

Vietinghoff¹,

Choi²,

Rolle³

et al. 2007

Arthritis & Rheumatism

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Objective. Neutrophil activation by antineutrophil cytoplasmic autoantibodies (ANCAs) is central to the pathogenesis of the ANCA-associated vasculitides. Febrile infections occur frequently during these diseases, often in the context of immunosuppressive treatment. Heat exposure may affect the underlying pathophysiologic processes of the vasculitis. In this study we tested the hypothesis that short-term exposure to heat inhibits ANCA-induced neutrophil activation.Methods. After exposure to temperatures from 37°C to 42°C, human neutrophils were primed with either tumor necrosis factor ␣ (TNF␣) or granulocytemacrophage colony-stimulating factor (GM-CSF) and stimulated with monoclonal antibodies to myeloperoxidase or to proteinase 3. Respiratory burst activity was assayed using rhodamine and a nitroblue tetrazolium reduction assay. Specific inhibition experiments against p38 MAPK, ERK, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt, and Western blotting with phosphospecific antibodies were used to identify key components in the antibody-induced respiratory burst.

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Section: Discussionsupporting

confidence: 65%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt

Vietinghoff¹,

Choi²,

Rolle³

et al. 2007

Arthritis & Rheumatism

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“…Akt was shown previously to be activated in human neutrophils by fMLP, leukotriene B4, IL-8, Fc␥R cross-linking, LPS, GM-CSF, and antineutrophil cytoplasmic Abs (18,30,(35)(36)(37). We report for the first time, that a GABA B R agonist, baclofen, stimulates Akt phosphorylation and activation in a PI3K-dependent manner, whereas CGP52432, a GABA B R antagonist inhibits baclofenstimulated Akt activation, suggesting a functional association of Akt and GABA B R in human neutrophils.…”

Section: Discussionmentioning

confidence: 97%

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

Rane

Gozal

Butt

et al. 2005

The Journal of Immunology

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Serine/threonine kinase Akt, or protein kinase B, has been shown to regulate a number of neutrophil functions. We sought to identify Akt binding proteins in neutrophils to provide further insights into understanding the mechanism by which Akt regulates various neutrophil functions. Proteomic and immunoprecipitation studies identified γ-amino butyric acid (GABA) type B receptor 2 (GABABR2) as an Akt binding protein in human neutrophils. Neutrophil lysates subjected to Akt immunoprecipitation followed by immunoblotting with anti-GABABR2 demonstrated Akt association with the intact GABABR. Similar results were obtained when reciprocal immunoprecipitations were performed with anti-GABABR2 Ab. Additionally, GABABR2 and Akt colocalization was demonstrated by confocal microscopy. A GABABR agonist, baclofen, activated Akt and stimulated neutrophil-directed migration in a PI3K-dependent manner, whereas CGP52432, a GABABR antagonist blocked such effects. Baclofen, stimulated neutrophil chemotaxis and tubulin reorganization in a PI3K-dependent manner. Additionally, a GABABR agonist failed to stimulate neutrophil superoxide burst. We are unaware of the association of GABABR with Akt in any cell type. The present study shows for the first time that a brain-specific receptor, GABABR2 is present in human neutrophils and that it is functionally associated with Akt. Intraventricular baclofen pretreatment in rats subjected to a stroke model showed increased migration of neutrophils to the ischemic lesion. Thus, the GABABR is functionally expressed in neutrophils, and acts as a chemoattractant receptor via an Akt-dependent pathway. The GABABR potentially plays a significant role in the inflammatory response and neutrophil-dependent ischemia-reperfusion injury such as stroke.

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“…ANCA are pathogenic in animal models and activate in vitro cytokine-primed neutrophils that express ANCA antigens (4,5,8,10,11,(23)(24)(25)(26). Neutrophil priming mobilizes PR3, the WG autoantigen, from its intracellular stores, resulting in an increased membrane expression.…”

Section: Discussionmentioning

confidence: 99%

Membrane Proteinase 3 Expression in Patients with Wegener’s Granulomatosis and in Human Hematopoietic Stem Cell–Derived Neutrophils

Schreiber

Otto

et al. 2005

Journal of the American Society of Nephrology

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A large membrane proteinase 3 (mPR3)-positive neutrophil subset (mPR3 high ) is a risk for Wegener's granulomatosis (WG).The relationship between mPR3 expression and clinical manifestations was investigated in 81 WG patients and mPR3 expression was studied in CD34 ؉ stem cell-derived human neutrophils. The mPR3 high neutrophil percentage correlated with renal function, anemia, and albumin at the time of presentation. The mPR3 high neutrophil percentage and renal failure severity correlated directly after 5 yr. For elucidating mechanisms that govern mPR3 expression, studies were conducted to determine whether the genetic information that governs mPR3 expression resides within the neutrophils, even without stimuli possibly related to disease. CD34 ؉ hematopoietic stem cells were differentiated to neutrophils, and their mPR3 expression was determined. A two-step amplification/differentiation protocol was used to differentiate human CD34 ؉ hematopoietic stem cells into neutrophils with G-CSF. The cells progressively expressed the neutrophil surface markers CD66b, CD35, and CD11b. The ferricytochrome C assay demonstrated a strong respiratory burst at day 14 in response to PMA but none at day 0. Intracellular PR3 was detectable from day 4 by Western blotting. An increasing percentage of a mPR3-positive neutrophil subset became detectable by flow cytometry, whereas a second subset remained negative, consistent with a bimodal expression. Finally, human PR3-anti-neutrophil cytoplasmic autoantibodies induced a stronger respiratory burst, compared with human control IgG in stem cell-derived neutrophils. Taken together, these studies underscore the clinical importance of the WG mPR3 phenotype. The surface mPR3 on resting cells is probably genetically determined rather than being dictated by external factors.

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Phosphatidylinositol 3-Kinase Controls Antineutrophil Cytoplasmic Antibodies—Induced Respiratory Burst in Human Neutrophils

Cited by 63 publications

References 28 publications

Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt

Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

Membrane Proteinase 3 Expression in Patients with Wegener’s Granulomatosis and in Human Hematopoietic Stem Cell–Derived Neutrophils

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