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Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein
Increased neutrophils and elevated level of circulating calprotectin are hallmarks of severe COVID-19 and they contribute to the dysregulated immune responses and cytokine storm in susceptible patients. However, the precise mechanism controlling calprotectin production during SARS-CoV-2 infection re...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9510782/ https://www.ncbi.nlm.nih.gov/pubmed/36172386 http://dx.doi.org/10.3389/fimmu.2022.996637 |
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author | Loh, Jia Tong Teo, Joey Kay Hui Lam, Kong-Peng |
author_facet | Loh, Jia Tong Teo, Joey Kay Hui Lam, Kong-Peng |
author_sort | Loh, Jia Tong |
collection | PubMed |
description | Increased neutrophils and elevated level of circulating calprotectin are hallmarks of severe COVID-19 and they contribute to the dysregulated immune responses and cytokine storm in susceptible patients. However, the precise mechanism controlling calprotectin production during SARS-CoV-2 infection remains elusive. In this study, we showed that Dok3 adaptor restrains calprotectin production by neutrophils in response to SARS-CoV-2 spike (S) protein engagement of TLR4. Dok3 recruits SHP-2 to mediate the de-phosphorylation of MyD88 at Y257, thereby attenuating downstream JAK2-STAT3 signaling and calprotectin production. Blocking of TLR4, JAK2 and STAT3 signaling could prevent excessive production of calprotectin by Dok3(-/-) neutrophils, revealing new targets for potential COVID-19 therapy. As S protein from SARS-CoV-2 Delta and Omicron variants can activate TLR4-driven calprotectin production in Dok3(-/-) neutrophils, our study suggests that targeting calprotectin production may be an effective strategy to combat severe COVID-19 manifestations associated with these emerging variants. |
format | Online Article Text |
id | pubmed-9510782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95107822022-09-27 Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein Loh, Jia Tong Teo, Joey Kay Hui Lam, Kong-Peng Front Immunol Immunology Increased neutrophils and elevated level of circulating calprotectin are hallmarks of severe COVID-19 and they contribute to the dysregulated immune responses and cytokine storm in susceptible patients. However, the precise mechanism controlling calprotectin production during SARS-CoV-2 infection remains elusive. In this study, we showed that Dok3 adaptor restrains calprotectin production by neutrophils in response to SARS-CoV-2 spike (S) protein engagement of TLR4. Dok3 recruits SHP-2 to mediate the de-phosphorylation of MyD88 at Y257, thereby attenuating downstream JAK2-STAT3 signaling and calprotectin production. Blocking of TLR4, JAK2 and STAT3 signaling could prevent excessive production of calprotectin by Dok3(-/-) neutrophils, revealing new targets for potential COVID-19 therapy. As S protein from SARS-CoV-2 Delta and Omicron variants can activate TLR4-driven calprotectin production in Dok3(-/-) neutrophils, our study suggests that targeting calprotectin production may be an effective strategy to combat severe COVID-19 manifestations associated with these emerging variants. Frontiers Media S.A. 2022-09-12 /pmc/articles/PMC9510782/ /pubmed/36172386 http://dx.doi.org/10.3389/fimmu.2022.996637 Text en Copyright © 2022 Loh, Teo and Lam 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 Loh, Jia Tong Teo, Joey Kay Hui Lam, Kong-Peng Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein |
title | Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein |
title_full | Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein |
title_fullStr | Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein |
title_full_unstemmed | Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein |
title_short | Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein |
title_sort | dok3 restrains neutrophil production of calprotectin during tlr4 sensing of sars-cov-2 spike protein |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9510782/ https://www.ncbi.nlm.nih.gov/pubmed/36172386 http://dx.doi.org/10.3389/fimmu.2022.996637 |
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