Phosphoinositide 3-kinase γ: a key modulator in inflammation and allergy

2003 ◽  
Vol 31 (1) ◽  
pp. 275-280 ◽  
Author(s):  
M.P. Wymann ◽  
K. Björklöf ◽  
R. Calvez ◽  
P. Finan ◽  
M. Thomast ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Function ◽  
Effector Cells ◽  
A3 Adenosine Receptor ◽  
Murine Mast Cell ◽  
Release Histamine ◽  
Granule Secretion ◽  
Phosphoinositide 3 Kinase

Chronic inflammation and allergy involve the activation of tissue-resident cells and, later on, the invasion of effector cells. We have previously shown that the loss of phosphoinositide 3-kinase (PI3K) γ impairs chemokine-dependent migration of neutrophils and macrophages both in vitro and in vivo. On the other hand, PI3Kγ is not required either during phagocytic processes or in the activation of bactericidal activities like granule secretion and particle-mediated respiratory burst in neutrophils. Tissue mast cells are key regulators in allergy and inflammation and release histamine upon clustering of their IgE receptors. We have demonstrated that murine mast cell responses are exacerbated in vitro and in vivo by autocrine signals, and require functional PI3Kγ. Adenosine, acting through the A3 adenosine receptor, as well as other agonists of Gαi-coupled receptors, transiently increased PtdIns(3,4,5)P3 exclusively via PI3Kγ. PI3Kγ-derived PtdIns(3,4,5)P3 was instrumental for initiation of a sustained influx of external Ca2+ and degranulation. Mice that lacked PI3Kγ did not form oedema when challenged by passive systemic anaphylaxis. PI3Kγ thus relays inflammatory signals through various GPCRs, and is thus central to mast cell function. Taken together, this suggests that pharmaceutical targeting of PI3Kγ might alleviate inflammation at both early and late stages of the allergic response.

scholarly journals p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 3951-3961 ◽  
Author(s):  
Subha Krishnan ◽  
Raghuveer Singh Mali ◽  
Baskar Ramdas ◽  
Emily Sims ◽  
Peilin Ma ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Function ◽  
Receptor Internalization ◽  
Regulatory Subunit ◽  
Growth Defects ◽  
Microphthalmia Transcription Factor ◽  
Carboxy Terminal

Abstract We show that loss of p85α inhibits the growth and maturation of mast cells, whereas loss of p85β enhances this process. Whereas restoring the expression of p85α in P85α−/− cells restores these functions, overexpression of p85β has the opposite effect. Consistently, overexpression of p85β in WT mast cells represses KIT-induced proliferation and IL-3–mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85α and p85β differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85α and/or p85β do not rescue the growth defects of p85α−/− cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85β impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85β relative to p85α. In vivo, loss of p85β resulted in increased mast cells, and bone marrow transplantation of cells overexpressing p85β resulted in significant reduction in some tissue mast cells. Overexpression of p85β suppressed the growth of oncogenic KIT-expressing cells in vitro and prolonged the survival of leukemic mice in vivo. Thus, p85α and p85β differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells.

scholarly journals Platelets are dispensable for the ability of CD8+ T cells to accumulate, patrol, kill and reside in the liver

2021 ◽  
Author(s):  
James H O'Connor ◽  
Hayley A McNamara ◽  
Yeping Cai ◽  
Lucy A Coupland ◽  
Elizabeth E Gardiner ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Protective Function ◽  
Memory Cd8 T Cells ◽  
Effector Cells ◽  
Large Numbers ◽  
Platelet Concentration

Effector and memory CD8+ T cells accumulate in large numbers in the liver where they play key roles in the control of liver pathogens including Plasmodium. It has also been proposed that liver may act as the main place for elimination of effector CD8+ T cells at the resolution of immune responses. Platelets and the integrin LFA-1 have been proposed to be critical for the accumulation of protective CD8+ T cells in the liver; conversely, asialo-glycoprotein (ASGP) expression on the surface of CD8+ T cells has been proposed to assist in elimination of effector T cells in the liver. Here we investigated the contributions of these interactions in the accumulation of CD8+ T cells activated in vitro or in vivo by immunization with Plasmodium parasites. Using Mpl-/- mice with constitutive thrombocytopaenia and antibody-mediated platelet depletion models we found that severe reduction in platelet concentration in circulation did not strongly influence the accumulation and protective function of CD8+ T cells in the liver in these models. Surprisingly, inhibition of ASGP receptors did not inhibit the accumulation of effector cells in the liver, but instead prevented these cells from accumulating in the spleen. We further found that enforced expression of ASGP on effector CD8+ T cells using St3GalI knockout cells lead to their loss from the spleen. These data suggest that platelets play a marginal role in CD8+ T cell function in the liver. Furthermore, ASGP-expressing effector CD8+ T cells are retained in the liver but are lost from the spleen.

scholarly journals Blunted IgE-mediated activation of mast cells in mice lacking the serum- and glucocorticoid-inducible kinase SGK3

2010 ◽  
Vol 299 (5) ◽  
pp. C1007-C1014 ◽  
Author(s):  
Irina M. Zemtsova ◽  
Nicole Heise ◽  
Henning Fröhlich ◽  
Syed M. Qadri ◽  
Yuliya Kucherenko ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Function ◽  
Sharp Decrease ◽  
Pi3 Kinase ◽  
Antigen Stimulation ◽  
Intracellular Ca ◽  
Cognate Antigen

Previous studies have shown that pharmacological inhibition of the phosphoinositol-3 (PI3) kinase disrupts the activation of mast cells. Through phosphoinositide-dependent kinase PDK1, PI3 kinase activates the serum- and glucocorticoid-inducible kinase 3 (SGK3). The present study explored the role of SGK3 in mast cell function. Mast cells were isolated and cultured from bone marrow (BMMCs) of gene-targeted mice lacking SGK3 ( sgk3 −/−) and their wild-type littermates ( sgk3 +/+). BMMC numbers in the ear conch were similar in both genotypes. Stimulation with IgE and cognate antigen triggered the release of intracellular Ca2+ and entry of extracellular Ca2+. Influx of extracellular Ca2+ but not Ca2+ release from intracellular stores was significantly blunted in sgk3 −/− BMMCs compared with sgk3 +/+ BMMCs. Antigen stimulation further led to a rapid increase of a K+-selective conductance in sgk3 +/+ BMMCs, an effect again blunted in sgk3 −/− BMMCs. In contrast, the Ca2+ ionophore ionomycin activated K+ currents to a similar extent in sgk3 −/− and in sgk3 +/+ BMMCs. β-Hexosaminidase release, triggered by antigen stimulation, was also significantly decreased in sgk3 −/− BMMCs. IgE-dependent anaphylaxis measured as a sharp decrease in body temperature upon injection of DNP-HSA antigen was again significantly blunted in sgk3 −/− compared with sgk3 +/+ mice. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk3 −/− than in sgk3 +/+ mice. In conclusion, both in vitro and in vivo function of BMMCs are impaired in gene targeted mice lacking SGK3. Thus SGK3 is critical for proper mast cell function.

scholarly journals Lactic acid suppresses IgE-mediated mast cell function in vitro and in vivo

2019 ◽  
Vol 341 ◽  
pp. 103918 ◽  
Author(s):  
Daniel Abebayehu ◽  
Andrew J. Spence ◽  
Heather Caslin ◽  
Marcela Taruselli ◽  
Tamara T. Haque ◽  
...  
Keyword(s):  
Mast Cell ◽  
Lactic Acid ◽  
Cell Function ◽  
Ige Mediated

Stat5B is Required for IgE-Mediated Mast Cell Function in vitro and in vivo

2021 ◽  
pp. 104344
Author(s):  
Kasalina N. Kiwanuka ◽  
E. Motunrayo Kolawole ◽  
Jamie Josephine Avila Mcleod ◽  
Bianca Baker ◽  
Patrick A. Paez ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Function ◽  
Ige Mediated

Abstract 41: Platelet Dream Plays a Critical Role During Thrombogenesis in Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Kyungho Kim ◽  
Alan Tseng ◽  
Andrew Barazia ◽  
Joseph E Italiano ◽  
Jaehyung Cho
Keyword(s):  
Thrombus Formation ◽  
Regulatory Element ◽  
Critical Role ◽  
Flow Chamber ◽  
Regulatory Function ◽  
Pi3k Activation ◽  
Granule Secretion ◽  
Phosphoinositide 3 Kinase

Downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor, is known to modulate pain. Using intravital microscopy with DREAM-null mice and their bone marrow chimeras, we demonstrated that hematopoietic and endothelial cell DREAM are required for platelet thrombus formation following arteriolar injury. DREAM deletion also prolonged tail bleeding times. In vitro flow chamber assays and in vivo adoptive transfer experiments indicated the importance of platelet DREAM in thrombogenesis. We found that deletion of platelet DREAM does not alter ultrastructural features but significantly impaired aggregation and ATP secretion induced by collagen-related peptide (CRP), ADP, or A23187, but not thrombin or U46619. Biochemical studies showed that platelet DREAM is required for phosphoinositide 3-kinase (PI3K) activation induced by GPVI-, A23187-, or integrin-mediated signaling. Studies using DREAM-null platelets and isoform-specific PI3K inhibitors revealed that platelet DREAM positively regulates granule secretion, Ca2+ mobilization, and aggregation induced by CRP or A23187 through PI3K class Iβ (PI3K-Iβ) activity. Genetic and pharmacological studies in megakaryoblastic MEG-01 cells showed that DREAM regulates A23187-induced Ca2+ mobilization and that the regulatory function of DREAM requires Ca2+ binding and PI3K-Iβ activity. Taken together, we have identified platelet DREAM as a novel regulator of PI3K-Iβ activity during thrombus formation.

scholarly journals Ruxolitinib partially reverses functional NK cell deficiency in patients withSTAT1gain-of-function mutations

2017 ◽  
Author(s):  
Alexander Vargas-Hernandez ◽  
Emily M. Mace ◽  
Ofer Zimmerman ◽  
Christa S. Zerbe ◽  
Alexandra F. Freeman ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Function ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Viral Susceptibility ◽  
And Function

AbstractBackgroundNatural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility.ObjectiveWe sought to investigate NK cell function in STAT1 GOF patients. Methods: NK cell phenotype and function were determined in 16 STAT1 GOF patients.MethodsNK cell phenotype and function were determined in 16 STAT1 GOF patients.NK cell lines expressing patient mutations were generated with CRISPR-Cas9 mediated gene editing. STAT1 GOF NK cells were treated in vitro with ruxolitinib.ResultsPeripheral blood NK cells from of STAT1 GOF patients had impaired terminal maturation. Specifically, patients withSTAT1 GOFmutations have immature CD56dimNK cells with decreased expression of CD16, perforin, CD57 and impaired cytolytic function. STAT1 phosphorylation was elevated but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT signaling with the small molecule JAK1/2 inhibitor ruxolitinibin vitroandin vivorestored perforin expression in CD56dimNK cells and partially restored NK cell cytotoxic function.ConclusionsProperly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of elevated STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients withSTAT1 GOFmutations.

scholarly journals T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 2894-2902 ◽  
Author(s):  
Jonathan A. Deane ◽  
Michael G. Kharas ◽  
Jean S. Oak ◽  
Linda N. Stiles ◽  
Ji Luo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Function ◽  
Pi3k Signaling ◽  
Regulatory Subunits ◽  
Cell Functions ◽  
Phosphoinositide 3 Kinase

Abstract The class IA subgroup of phosphoinositide 3-kinase (PI3K) is activated downstream of antigen receptors, costimulatory molecules, and cytokine receptors on lymphocytes. Targeted deletion of individual genes for class IA regulatory subunits severely impairs the development and function of B cells but not T cells. Here we analyze conditional mutant mice in which thymocytes and T cells lack the major class IA regulatory subunits p85α, p55α, p50α, and p85β. These cells exhibit nearly complete loss of PI3K signaling downstream of the T-cell receptor (TCR) and CD28. Nevertheless, T-cell development is largely unperturbed, and peripheral T cells show only partial impairments in proliferation and cytokine production in vitro. Both genetic and pharmacologic experiments suggest that class IA PI3K signaling plays a limited role in T-cell proliferation driven by TCR/CD28 clustering. In vivo, class IA–deficient T cells provide reduced help to B cells but show normal ability to mediate antiviral immunity. Together these findings provide definitive evidence that class IA PI3K regulatory subunits are essential for a subset of T-cell functions while challenging the notion that this signaling mechanism is a critical mediator of costimulatory signals downstream of CD28.

FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 3997-4002 ◽  
Author(s):  
Dirk Meyer ◽  
Carsten Schiller ◽  
Jürgen Westermann ◽  
Shozo Izui ◽  
Wouter L. W. Hazenbos ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Knock Out ◽  
Effector Cells ◽  
Igg Isotypes ◽  
Knock Out Mice ◽  
Deficient Mice ◽  
Experimental Autoimmune

Abstract In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcγRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.

scholarly journals A cloned cell line mediating natural killer cell function inhibits immunoglobulin secretion.

1982 ◽  
Vol 156 (2) ◽  
pp. 658-663 ◽  
Author(s):  
G Nabel ◽  
W J Allard ◽  
H Cantor
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Line ◽  
B Lymphocytes ◽  
Cell Function ◽  
Killer Cell ◽  
Major Histocompatibility Complex Gene ◽  
Cell Surface Antigens

We previously described a cloned cell line that combines information for a unique display of cell surface antigens and specialized function similar to activated natural killer (NK) cells. In addition to conventional cellular targets such as the YAC-1 and MBL-2 lymphomas, this cloned line also lysed lipopolysaccharide-activated B lymphocytes. To determine whether some NK cells can inhibit B cell function, we tested the ability of NK-like clones to suppress Ig secretion in vitro and in vivo. These cloned cells suppressed Ig secretion when they constituted as few as 0.2% of the total cell population and inhibition did not require identity at the H-2 locus. We suggest that some NK cells might recognize non-major histocompatibility complex gene products on activated B lymphocytes and lyse these cells, and this might represent a fundamental cell-cell interaction that regulates antibody secretion by activated B cells.

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