Mitochondrial STAT3 plays a major role in IgE-antigen–mediated mast cell exocytosis

Erlich, Tal Hadad; Yagil, Zohar; Kay, Gillian; Peretz, Alona; Migalovich-Sheikhet, Helena; Tshori, Sagi; Nechushtan, Hovav; Levi‐Schaffer, Francesca; Saada, Ann; Razin, Ehud

doi:10.1016/j.jaci.2013.12.1075

Cited by 68 publications

(95 citation statements)

References 42 publications

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“…Although mitochondrial STAT3 has been shown to play a role in IgE-antigen mediated mast cell degranulation 10 in rodent models, in the present study STAT3 inhibition did not result in a detectable difference in circulating mast cell mediators (histamine, MCPT1) in an in vivo anaphylaxis model, or defective β-hexosaminidase release in vitro in a mast cell activation assay. These differences may be reconciled by the fact that Erlich et al mainly used different concentrations of inhibitor and different cell lines that may have resulted in different on- and off-target effects.…”

Section: Discussioncontrasting

confidence: 76%

“…Dominant negative STAT3 mutations in humans result in dermatitis, elevated serum IgE, enhanced susceptibility to staphylococcal skin and respiratory infection, mucocutaneous candidiasis, and connective tissue and skeletal abnormalities 8 . Despite a significant burden of eczematous skin disease and associated elevations in both total and allergen-specific serum IgE, clinical food allergy and anaphylaxis are markedly diminished in patients with AD-HIES 9 .. One potential mechanism contributing to this phenomenon may involve STAT3-mediated regulation of mast cell degranulation 9 and mitochondrial activity 10 …”

Section: Introductionmentioning

confidence: 99%

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Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Hox

O’Connell

Lyons

et al. 2016

Journal of Allergy and Clinical Immunology

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Background During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have previously demonstrated that patients and mice with STAT3 mutations (autosomal dominant-hyper IgE syndrome; AD-HIES) are partially protected from anaphylaxis. Objectives To further study the mechanism by which STAT3 contributes to anaphylaxis, and determine whether small molecule inhibition of STAT3 can prevent anaphylaxis. Methods Using unaffected and STAT3-inhibited or genetic loss of function samples, we performed histamine skin prick testing, investigated the contribution of STAT3 to animal models of anaphylaxis, measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. Results While mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant AD-HIES mice and in wild-type mice subjected to small molecule STAT3 inhibition. Histamine skin prick responses were diminished in AD-HIES patients. Human umbilical vein vascular endothelial cells (HUVECs) derived from patients with AD-HIES or treated with a STAT3 inhibitor failed to properly signal through Src or to appropriately dissolute the adherens junctions made up of the proteins vascular endothelial (VE)-cadherin and β-catenin. Further, we found that diminished STAT3-target mir17–92 expression in AD-HIES HUVECS is associated with increased PTEN expression, which inhibits Src, and increased E2F1 expression, which regulates β-catenin cellular dynamics. Conclusions These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions thus permitting vascular permeability.

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Section: Discussioncontrasting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Hox

O’Connell

Lyons

et al. 2016

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…Intriguingly, our data suggest that these metabolic changes are actively induced by mast cells to carry out specific tasks. Our findings are intriguing in light of the observations that mast cell mitochondria translocate to the site of exocytosis during degranulation (20), and that mitochondrial STAT3 is responsible for induction of mitochondrial oxidative phosphorylation, ATP synthesis and subsequent degranulation (21). …”

Section: Resultsmentioning

confidence: 84%

Cutting Edge: Murine Mast Cells Rapidly Modulate Metabolic Pathways Essential for Distinct Effector Functions

Phong

Avery

Menk

et al. 2017

The Journal of Immunology

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There is growing appreciation that cellular metabolic and bioenergetic pathways do not play merely passive roles in activated leukocytes. Rather, metabolism plays important roles in controlling cellular activation, differentiation, survival and effector function. Much of this work has been performed in T cells; however, there is still very little information regarding mast cell metabolic reprogramming and its effect on cellular function. Mast cells perform important barrier functions and help control type 2 immune responses. Here we show here that murine bone marrow derived mast cells rapidly alter their metabolism in response to stimulation through the Fc receptor for IgE (FcεRI). We also demonstrate that specific metabolic pathways appear to be differentially required for control of mast cell function. Manipulation of metabolic pathways may represent a novel point for manipulation of mast cell activation.

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“…IgE düzeyinde artışa neden olan mekanizma tam olarak aydınlatılmamış olsa da uygunsuz IL4 üretimi sorumlu tutulmuştur (37). Yüksek serum IgE düzeylerine rağmen klinik olarak allerjik hastalık varlığı ve anaflaksi oldukça nadirdir (13,(38)(39)(40). Benzer şekilde bizim olgularımızdan STAT3 gen mutasyonu taşıyanlarda allerjene duyarlanma saptanmamıştır.…”

Section: Discussionunclassified

Serum IgE Düzeyi ve Eozinofil Sayısı ile Atopik Hastalıklar Hiper IgE Sendromu’ndan Ayırt Edilebilir mi?

Kıykım¹,

Yüce²,

Baris³

et al. 2017

Asthma Allergy Immunol

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Mitochondrial STAT3 plays a major role in IgE-antigen–mediated mast cell exocytosis

Cited by 68 publications

References 42 publications

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

Cutting Edge: Murine Mast Cells Rapidly Modulate Metabolic Pathways Essential for Distinct Effector Functions

Serum IgE Düzeyi ve Eozinofil Sayısı ile Atopik Hastalıklar Hiper IgE Sendromu’ndan Ayırt Edilebilir mi?

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