IgA Fc receptor (CD89) activation enables coupling to syk and Btk tyrosine kinase pathways: differential signaling after IFN-γ or phorbol ester stimulation

Launay, Pierre; Lehuen, Agnès; Kawakami, Toshiaki; Blank, Ulrich; Monteiro, Renato C.

doi:10.1002/jlb.63.5.636

Cited by 50 publications

(34 citation statements)

References 31 publications

(41 reference statements)

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“…Both ITAM-dependent (49) and ITAM-independent inflammatory responses can be negatively regulated by this receptor. The inhibitory mechanism involves activation of SHP-1 likely by neutralizing receptor-activated phosphorylation responses.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

Kanamaru

Pfirsch

Aloulou

et al. 2008

The Journal of Immunology

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Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcαRI or CD89) by anti-FcαRI Fab triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain (FcαRI-FcRγ ITAMi) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcαRI-FcRγ ITAMi signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcαRI-Fcγ ITAMi signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcαRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcαRI-FcRγ ITAMi signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcαRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

Kanamaru

Pfirsch

Aloulou

et al. 2008

The Journal of Immunology

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“…Antibody 17.3 recognizes also a p28 in addition to PLSCR1 (33). Rabbit antiSyk polyclonal antibody has been described (34). Anti-phosphotyrosine monoclonal antibody 4G10 was used as a culture supernatant of the 4G10 hybridoma or as horseradish peroxidase-coupled antibody (Calbiochem, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

Phospholipid Scramblase 1 Modulates a Selected Set of IgE Receptor-mediated Mast Cell Responses through LAT-dependent Pathway

Amir-Moazami¹,

Alexia²,

Charles³

et al. 2008

Journal of Biological Chemistry

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Engagement of the IgE receptor (Fc⑀RI) on mast cells leads to the release of preformed and newly formed mediators as well as of cytokines. The signaling pathways responsible for these responses involve tyrosine phosphorylation of multiple proteins. We previously reported the phosphorylation on tyrosine of phospholipid scramblase 1 (PLSCR1) after Fc⑀RI aggregation. Here, PLSCR1 expression was knocked down in the RBL-2H3 mast cell line using short hairpin RNA. Knocking down PLSCR1 expression resulted in significantly impaired degranulation responses after Fc⑀RI aggregation and release of vascular endothelial growth factor, whereas release of MCP-1 was minimally affected. The release of neither leukotriene C4 nor prostaglandin D2 was altered by knocking down of PLSCR1. Analysis of Fc⑀RI-dependent signaling pathways revealed that whereas tyrosine phosphorylation of ERK and Akt was unaffected, tyrosine phosphorylation of LAT was significantly reduced in PLSCR1 knocked down cells. Tyrosine phosphorylation of phospholipase C␥1 and consequently the mobilization of calcium were also significantly reduced in these cells. In nonactivated mast cells, PLSCR1 was found in part in lipid rafts where it was further recruited after cell activation and was constitutively associated with Lyn and Syk but not with LAT or Fyn. Altogether, these data identify PLSCR1 as a novel amplifier of Fc⑀RI signaling that acts selectively on the Lyn-initiated LAT/phospholipase C␥1/calcium axis, resulting in potentiation of a selected set of mast cell responses.Mast cells actively participate in the defense against bacterial and parasitic infections (1, 2) and are key players in the allergic reaction. They express receptors that bind IgE with a high affinity (Fc⑀RI) and that are aggregated by the cognate allergen when they are occupied by allergen-specific IgE (3). This results in a number of cellular responses, such as immediate release of granule contents (e.g. histamine and ␤-hexosaminidase), synthesis of the lipid mediators of inflammation leukotrienes (LT) 6 and prostaglandins (PG), and delayed production and release of cytokines and chemokines (4).The pathways leading from Fc⑀RI aggregation to cellular responses have been extensively studied and depend on tyrosine phosphorylations (5, 6). The two main pathways involve tyrosine kinases belonging to the Src family, Lyn and Fyn (4). Lyn is constitutively associated with Fc⑀RI ␤ chain (7). Upon aggregation of the receptor it phosphorylates both the ␤ and the ␥ chains of Fc⑀RI on tyrosine residues within the immunoreceptor tyrosine-based activation motif that is found in their intracellular domains (8). This results in the recruitment of additional Lyn molecules and of the tyrosine kinase Syk to the phosphorylated receptors and in the activation of Syk (9 -11). Lyn and Syk then phosphorylate a number of substrates including the scaffold proteins LAT (12) and LAT2 (13-15). Activation of PLC␥1 and PLC␥2 recruited to phosphorylated LAT leads to the release in the cytosol of inositol 1,4,5-trisphospha...

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“…We tested the possible effect of (Ϫ)-nilvadipine on RAS activity and found that (Ϫ)-nilvadipine was unable to affect RAS activity in a cellfree assay ruling out RAS as a possible target of (Ϫ)-nilvadipine (data not shown). Tyrosine kinases, including Syk and Bruton's tyrosine kinase (BTK), are activated following PMA treatment (49,50), act upstream of RAS/RAF (51,52), and mediate the activation of the NFB pathway (53). We tested a selective BTK inhibitor (BTK inhibitor III, 1-(3-(4-amino-3-(4-phenyloxy phenyl)-1H-pyrazolo [3,4- [3,4-d]pyrimidin-1-yl)piperidine) on A␤ production, and we found that this compound was unable to significantly inhibit A␤ production (data not shown) suggesting that the A␤-lowering properties of nilvadipine are not mediated via an inhibition of BTK.…”

Section: In Vitro Effects Of Nilvadipine Enantiomers On A␤ Productionmentioning

confidence: 99%

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Paris

Ait‐Ghezala

Bachmeier

et al. 2014

Journal of Biological Chemistry

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Background: Spleen tyrosine kinase (Syk) mediates microglial activation and neurotoxicity elicited by Alzheimer A␤ peptides. Results: Syk regulates A␤ production via NFB-dependent mechanisms and Tau phosphorylation by controlling the activation of glycogen synthase 3␤. Conclusion: Inhibition of Syk can interrupt the neuroinflammation, pathological A␤ accumulation, and Tau hyperphosphorylation in AD. Significance: Syk represents a therapeutic target for the key pathological lesions that define AD.

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IgA Fc receptor (CD89) activation enables coupling to syk and Btk tyrosine kinase pathways: differential signaling after IFN-γ or phorbol ester stimulation

Cited by 50 publications

References 31 publications

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

Phospholipid Scramblase 1 Modulates a Selected Set of IgE Receptor-mediated Mast Cell Responses through LAT-dependent Pathway

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

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