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SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response

Binding of antigen to IgE-high affinity FcεRI complexes on mast cells and basophils results in the release of preformed mediators such as histamine and de novo synthesis of cytokines causing allergic reactions. Src-like adapter protein (SLAP) functions co-operatively with c-Cbl to negatively regulat...

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Autores principales: Sharma, Namit, Ponce, Marta, Kaul, Savar, Pan, Zhongda, Berry, Donna M., Eiwegger, Thomas, McGlade, Catherine J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529641/
https://www.ncbi.nlm.nih.gov/pubmed/31156621
http://dx.doi.org/10.3389/fimmu.2019.01020
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author Sharma, Namit
Ponce, Marta
Kaul, Savar
Pan, Zhongda
Berry, Donna M.
Eiwegger, Thomas
McGlade, Catherine J.
author_facet Sharma, Namit
Ponce, Marta
Kaul, Savar
Pan, Zhongda
Berry, Donna M.
Eiwegger, Thomas
McGlade, Catherine J.
author_sort Sharma, Namit
collection PubMed
description Binding of antigen to IgE-high affinity FcεRI complexes on mast cells and basophils results in the release of preformed mediators such as histamine and de novo synthesis of cytokines causing allergic reactions. Src-like adapter protein (SLAP) functions co-operatively with c-Cbl to negatively regulate signaling downstream of the T cell receptor, B cell receptor, and receptor tyrosine kinases (RTK). Here, we investigated the role of SLAP in FcεRI-mediated mast cell signaling, using bone marrow derived mast cells (BMMCs) from SLAP knock out (SLAP KO) mice. Mature SLAP-KO BMMCs displayed significantly enhanced antigen induced degranulation and synthesis of IL-6, TNFα, and MCP-1 compared to wild type (WT) BMMCs. In addition, SLAP KO mice displayed an enhanced passive cutaneous anaphylaxis response. In agreement with a negative regulatory role, SLAP KO BMMCs showed enhanced FcεRI-mediated signaling to downstream effector kinases, Syk, Erk, and Akt. Recombinant GST-SLAP protein binds to the FcεRIβ chain and to the Cbl-b in mast cell lysates, suggesting a role in FcεRI down regulation. In addition, the ubiquitination of FcεRIγ chain and antigen mediated down regulation of FcεRI is impaired in SLAP KO BMMCs compared to the wild type. In line with these findings, stimulation of peripheral blood human basophils with FcεRIα antibody, or a clinically relevant allergen, resulted in increased SLAP expression. Together, these results indicate that SLAP is a dynamic regulator of IgE-FcεRI signaling, limiting allergic responses.
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spelling pubmed-65296412019-05-31 SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response Sharma, Namit Ponce, Marta Kaul, Savar Pan, Zhongda Berry, Donna M. Eiwegger, Thomas McGlade, Catherine J. Front Immunol Immunology Binding of antigen to IgE-high affinity FcεRI complexes on mast cells and basophils results in the release of preformed mediators such as histamine and de novo synthesis of cytokines causing allergic reactions. Src-like adapter protein (SLAP) functions co-operatively with c-Cbl to negatively regulate signaling downstream of the T cell receptor, B cell receptor, and receptor tyrosine kinases (RTK). Here, we investigated the role of SLAP in FcεRI-mediated mast cell signaling, using bone marrow derived mast cells (BMMCs) from SLAP knock out (SLAP KO) mice. Mature SLAP-KO BMMCs displayed significantly enhanced antigen induced degranulation and synthesis of IL-6, TNFα, and MCP-1 compared to wild type (WT) BMMCs. In addition, SLAP KO mice displayed an enhanced passive cutaneous anaphylaxis response. In agreement with a negative regulatory role, SLAP KO BMMCs showed enhanced FcεRI-mediated signaling to downstream effector kinases, Syk, Erk, and Akt. Recombinant GST-SLAP protein binds to the FcεRIβ chain and to the Cbl-b in mast cell lysates, suggesting a role in FcεRI down regulation. In addition, the ubiquitination of FcεRIγ chain and antigen mediated down regulation of FcεRI is impaired in SLAP KO BMMCs compared to the wild type. In line with these findings, stimulation of peripheral blood human basophils with FcεRIα antibody, or a clinically relevant allergen, resulted in increased SLAP expression. Together, these results indicate that SLAP is a dynamic regulator of IgE-FcεRI signaling, limiting allergic responses. Frontiers Media S.A. 2019-05-15 /pmc/articles/PMC6529641/ /pubmed/31156621 http://dx.doi.org/10.3389/fimmu.2019.01020 Text en Copyright © 2019 Sharma, Ponce, Kaul, Pan, Berry, Eiwegger and McGlade. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Sharma, Namit
Ponce, Marta
Kaul, Savar
Pan, Zhongda
Berry, Donna M.
Eiwegger, Thomas
McGlade, Catherine J.
SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response
title SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response
title_full SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response
title_fullStr SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response
title_full_unstemmed SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response
title_short SLAP Is a Negative Regulator of FcεRI Receptor-Mediated Signaling and Allergic Response
title_sort slap is a negative regulator of fcεri receptor-mediated signaling and allergic response
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529641/
https://www.ncbi.nlm.nih.gov/pubmed/31156621
http://dx.doi.org/10.3389/fimmu.2019.01020
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