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RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils
As first responder cells in host defense, neutrophils must be carefully regulated to prevent collateral tissue injury. However, the intracellular events that titrate the neutrophil’s response to inflammatory stimuli remain poorly understood. As a molecular switch, Ras activity is tightly regulated b...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579101/ https://www.ncbi.nlm.nih.gov/pubmed/34777356 http://dx.doi.org/10.3389/fimmu.2021.744300 |
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author | Saito, Suguru Cao, Duo-Yao Victor, Aaron R. Peng, Zhenzi Wu, Hui-Ya Okwan-Duodu, Derick |
author_facet | Saito, Suguru Cao, Duo-Yao Victor, Aaron R. Peng, Zhenzi Wu, Hui-Ya Okwan-Duodu, Derick |
author_sort | Saito, Suguru |
collection | PubMed |
description | As first responder cells in host defense, neutrophils must be carefully regulated to prevent collateral tissue injury. However, the intracellular events that titrate the neutrophil’s response to inflammatory stimuli remain poorly understood. As a molecular switch, Ras activity is tightly regulated by Ras GTPase activating proteins (RasGAP) to maintain cellular active-inactive states. Here, we show that RASAL3, a RasGAP, is highly expressed in neutrophils and that its expression is upregulated by exogenous stimuli in neutrophils. RASAL3 deficiency triggers augmented neutrophil responses and enhanced immune activation in acute inflammatory conditions. Consequently, mice lacking RASAL3 (RASAL3-KO) demonstrate accelerated mortality in a septic shock model via induction of severe organ damage and hyperinflammatory response. The excessive neutrophilic hyperinflammation and increased mortality were recapitulated in a mouse model of sickle cell disease, which we found to have low neutrophil RASAL3 expression upon LPS activation. Thus, RASAL3 functions as a RasGAP that negatively regulates the cellular activity of neutrophils to modulate the inflammatory response. These results demonstrate that RASAL3 could serve as a therapeutic target to regulate excessive inflammation in sepsis and many inflammatory disease states. |
format | Online Article Text |
id | pubmed-8579101 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85791012021-11-11 RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils Saito, Suguru Cao, Duo-Yao Victor, Aaron R. Peng, Zhenzi Wu, Hui-Ya Okwan-Duodu, Derick Front Immunol Immunology As first responder cells in host defense, neutrophils must be carefully regulated to prevent collateral tissue injury. However, the intracellular events that titrate the neutrophil’s response to inflammatory stimuli remain poorly understood. As a molecular switch, Ras activity is tightly regulated by Ras GTPase activating proteins (RasGAP) to maintain cellular active-inactive states. Here, we show that RASAL3, a RasGAP, is highly expressed in neutrophils and that its expression is upregulated by exogenous stimuli in neutrophils. RASAL3 deficiency triggers augmented neutrophil responses and enhanced immune activation in acute inflammatory conditions. Consequently, mice lacking RASAL3 (RASAL3-KO) demonstrate accelerated mortality in a septic shock model via induction of severe organ damage and hyperinflammatory response. The excessive neutrophilic hyperinflammation and increased mortality were recapitulated in a mouse model of sickle cell disease, which we found to have low neutrophil RASAL3 expression upon LPS activation. Thus, RASAL3 functions as a RasGAP that negatively regulates the cellular activity of neutrophils to modulate the inflammatory response. These results demonstrate that RASAL3 could serve as a therapeutic target to regulate excessive inflammation in sepsis and many inflammatory disease states. Frontiers Media S.A. 2021-10-27 /pmc/articles/PMC8579101/ /pubmed/34777356 http://dx.doi.org/10.3389/fimmu.2021.744300 Text en Copyright © 2021 Saito, Cao, Victor, Peng, Wu and Okwan-Duodu https://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 Saito, Suguru Cao, Duo-Yao Victor, Aaron R. Peng, Zhenzi Wu, Hui-Ya Okwan-Duodu, Derick RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils |
title | RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils |
title_full | RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils |
title_fullStr | RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils |
title_full_unstemmed | RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils |
title_short | RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils |
title_sort | rasal3 is a putative rasgap modulating inflammatory response by neutrophils |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579101/ https://www.ncbi.nlm.nih.gov/pubmed/34777356 http://dx.doi.org/10.3389/fimmu.2021.744300 |
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