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Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response

BACKGROUND: Previous studies have revealed an important role for the transcription factor GATA-1 in mast cell maturation and degranulation. However, there have been conflicting reports with respect to the requirement of GATA-1 function in mast cell dependent inflammatory processes. Herein, we examin...

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Autores principales: Sharma, Sribava, Tomar, Sunil, Dharne, Mayuri, Ganesan, Varsha, Smith, Andrew, Yang, Yanfen, Waggoner, Lisa, Wang, Yui-Hsi, Hogan, Simon P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675080/
https://www.ncbi.nlm.nih.gov/pubmed/31369572
http://dx.doi.org/10.1371/journal.pone.0219375
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author Sharma, Sribava
Tomar, Sunil
Dharne, Mayuri
Ganesan, Varsha
Smith, Andrew
Yang, Yanfen
Waggoner, Lisa
Wang, Yui-Hsi
Hogan, Simon P.
author_facet Sharma, Sribava
Tomar, Sunil
Dharne, Mayuri
Ganesan, Varsha
Smith, Andrew
Yang, Yanfen
Waggoner, Lisa
Wang, Yui-Hsi
Hogan, Simon P.
author_sort Sharma, Sribava
collection PubMed
description BACKGROUND: Previous studies have revealed an important role for the transcription factor GATA-1 in mast cell maturation and degranulation. However, there have been conflicting reports with respect to the requirement of GATA-1 function in mast cell dependent inflammatory processes. Herein, we examine the requirement of GATA-1 signaling in mast cell effector function and IgE-mast cell-dependent anaphylaxis. OBJECTIVE: To study the requirement of GATA-1 dependent signaling in the development and severity of IgE-mast cell-dependent anaphylaxis in mice. METHODS: Wild type (Balb/c) and mutant ΔdblGata (Balb/c) mice were employed to study the role of GATA-1 signaling in in vitro IgE-mediated activation of bone marrow derived mast cells (BMMCs). Murine models of passive IgE-mediated and oral antigen-induced IgE-mediated anaphylaxis were employed in mice. Frequency of steady state mast cells in various tissues (duodenum, ear, and tongue), peritoneal cavity, and clinical symptoms (diarrhea, shock, and mast cell activation) and intestinal Type 2 immune cell analysis including CD4(+) Th(2) cells, type 2 innate lymphoid cells (ILC2), and IL-9 secreting mucosal mast cells (MMC9) were assessed RESULTS: In vitro analysis revealed that ΔdblGata BMMCs exhibit a reduced maturation rate, decreased expression of FcεRIα, and degranulation capacity when compared to their wildtype (WT) counterparts. These in vitro differences did not impact tissue resident mast cell numbers, total IgE, and susceptibility to or severity of IgE-mediated passive anaphylaxis. Surprisingly, ΔdblGata mice were more susceptible to IgE-mast cell-mediated oral antigen induced anaphylaxis. The increased allergic response was associated with increased Type 2 immunity (antigen-specific IgE, and CD4(+) T(H)2 cells), MMC9 cells and small intestine (SI) mast cell load. CONCLUSION: Diminished GATA-1 activity results in reduced in vitro mast cell FcεRIα expression, proliferation, and degranulation activity. However, in vivo, diminished GATA-1 activity results in normal homeostatic tissue mast cell levels and increased antigen-induced CD4(+) Th2 and iMMC9 cell levels and heightened IgE-mast cell mediated reactions.
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spelling pubmed-66750802019-08-06 Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response Sharma, Sribava Tomar, Sunil Dharne, Mayuri Ganesan, Varsha Smith, Andrew Yang, Yanfen Waggoner, Lisa Wang, Yui-Hsi Hogan, Simon P. PLoS One Research Article BACKGROUND: Previous studies have revealed an important role for the transcription factor GATA-1 in mast cell maturation and degranulation. However, there have been conflicting reports with respect to the requirement of GATA-1 function in mast cell dependent inflammatory processes. Herein, we examine the requirement of GATA-1 signaling in mast cell effector function and IgE-mast cell-dependent anaphylaxis. OBJECTIVE: To study the requirement of GATA-1 dependent signaling in the development and severity of IgE-mast cell-dependent anaphylaxis in mice. METHODS: Wild type (Balb/c) and mutant ΔdblGata (Balb/c) mice were employed to study the role of GATA-1 signaling in in vitro IgE-mediated activation of bone marrow derived mast cells (BMMCs). Murine models of passive IgE-mediated and oral antigen-induced IgE-mediated anaphylaxis were employed in mice. Frequency of steady state mast cells in various tissues (duodenum, ear, and tongue), peritoneal cavity, and clinical symptoms (diarrhea, shock, and mast cell activation) and intestinal Type 2 immune cell analysis including CD4(+) Th(2) cells, type 2 innate lymphoid cells (ILC2), and IL-9 secreting mucosal mast cells (MMC9) were assessed RESULTS: In vitro analysis revealed that ΔdblGata BMMCs exhibit a reduced maturation rate, decreased expression of FcεRIα, and degranulation capacity when compared to their wildtype (WT) counterparts. These in vitro differences did not impact tissue resident mast cell numbers, total IgE, and susceptibility to or severity of IgE-mediated passive anaphylaxis. Surprisingly, ΔdblGata mice were more susceptible to IgE-mast cell-mediated oral antigen induced anaphylaxis. The increased allergic response was associated with increased Type 2 immunity (antigen-specific IgE, and CD4(+) T(H)2 cells), MMC9 cells and small intestine (SI) mast cell load. CONCLUSION: Diminished GATA-1 activity results in reduced in vitro mast cell FcεRIα expression, proliferation, and degranulation activity. However, in vivo, diminished GATA-1 activity results in normal homeostatic tissue mast cell levels and increased antigen-induced CD4(+) Th2 and iMMC9 cell levels and heightened IgE-mast cell mediated reactions. Public Library of Science 2019-08-01 /pmc/articles/PMC6675080/ /pubmed/31369572 http://dx.doi.org/10.1371/journal.pone.0219375 Text en © 2019 Sharma et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sharma, Sribava
Tomar, Sunil
Dharne, Mayuri
Ganesan, Varsha
Smith, Andrew
Yang, Yanfen
Waggoner, Lisa
Wang, Yui-Hsi
Hogan, Simon P.
Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response
title Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response
title_full Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response
title_fullStr Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response
title_full_unstemmed Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response
title_short Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response
title_sort deletion of δdblgata motif leads to increased predisposition and severity of ige-mediated food-induced anaphylaxis response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675080/
https://www.ncbi.nlm.nih.gov/pubmed/31369572
http://dx.doi.org/10.1371/journal.pone.0219375
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