Fc? receptor engagement by IgG is critical to activating myeloid cells during the inflammatory response. We find that IgG signaling requires Fyn kinase and is suppressed by Lyn. This is consistent in a model of Fc? receptor (Fc?R)-induced anaphylactic shock, where Lyn deletion exacerbates the response. We noted that Fc?R activated Stat5, whose deletion greatly reduced cytokine production. Fc?R responses are modified by cytokines. For example, IL-4 enhances inflammatory IgG receptor expression and cytokine secretion. In contrast, TGF1 antagonizes cytokine production and selectively decreases Fyn and Stat5 expression. TGF1 effects are absent in mast cells from Th2-prone mice, correlating with a lack of TGF-induced microRNAs capable of targeting Fyn and Stat5. We hypothesize that IL-4 and TGF1 regulate IgG-mediated inflammation partly by controlling the Fyn/Lyn-Stat5 pathway. Dysregulated IgG-mediated signaling, perhaps due to genetically predisposed responses to cytokines, may serve as the etiologic origin of inflammatory arthritis. We will test this hypothesis with mechanistic experiments in vitro and functional assays in vivo.
Our Specific Aims are: I. To test the hypothesis that Fyn and Lyn provide antagonistic control of Fc?R signaling, including the Stat5 pathway. II. To test the hypothesis that Fc?R-mediated inflammation is controlled by a cytokine network that includes IL-4 and TGF1.

Public Health Relevance

We will test the hypothesis that the kinases Fyn and Lyn provide antagonistic control of the critical transcription factor Stat5 during IgG-mediated signaling. This pathway can be regulated by cytokines, which collectively influence protective and pathological IgG responses, including those causing autoimmune arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI101153-05
Application #
9213342
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Peyman, John A
Project Start
2013-03-15
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
5
Fiscal Year
2017
Total Cost
$443,221
Indirect Cost
$147,263
Name
Virginia Commonwealth University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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McLeod, Jamie Josephine Avila; Caslin, Heather L; Spence, Andrew J et al. (2017) Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NF?B and AP-1 transcription. Cell Immunol 322:41-48
Caslin, Heather L; McLeod, Jamie Josephine Avila; Spence, Andrew J et al. (2017) Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IL-33-induced cytokine production in primary mouse mast cells. Cell Immunol 319:10-16
Ndaw, Victor S; Abebayehu, Daniel; Spence, Andrew J et al. (2017) TGF-?1 Suppresses IL-33-Induced Mast Cell Function. J Immunol 199:866-873
Abebayehu, Daniel; Spence, Andrew; Boyan, Barbara D et al. (2017) Galectin-1 promotes an M2 macrophage response to polydioxanone scaffolds. J Biomed Mater Res A 105:2562-2571
Kolawole, Elizabeth Motunrayo; McLeod, Jamie Josephine Avila; Ndaw, Victor et al. (2016) Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects. J Immunol 196:1461-70
Paranjape, Anuya; Chernushevich, Oksana; Qayum, Amina Abdul et al. (2016) Dexamethasone rapidly suppresses IL-33-stimulated mast cell function by blocking transcription factor activity. J Leukoc Biol 100:1395-1404
Abebayehu, Daniel; Spence, Andrew J; Qayum, Amina Abdul et al. (2016) Lactic Acid Suppresses IL-33-Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1?-Dependent miR-155 Suppression. J Immunol 197:2909-17
Qayum, Amina Abdul; Paranjape, Anuya; Abebayehu, Daniel et al. (2016) IL-10-Induced miR-155 Targets SOCS1 To Enhance IgE-Mediated Mast Cell Function. J Immunol 196:4457-67
McLeod, Jamie J A; Baker, Bianca; Ryan, John J (2015) Mast cell production and response to IL-4 and IL-13. Cytokine 75:57-61

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