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C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling
Critical illness is accompanied by the release of large amounts of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of neutrophils which is associated with adverse outcomes. The signaling pathways that mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy dono...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455072/ https://www.ncbi.nlm.nih.gov/pubmed/32634128 http://dx.doi.org/10.1172/jci.insight.137029 |
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author | Wood, Alexander J.T. Vassallo, Arlette M. Ruchaud-Sparagano, Marie-Hélène Scott, Jonathan Zinnato, Carmelo Gonzalez-Tejedo, Carmen Kishore, Kamal D’Santos, Clive S. Simpson, A. John Menon, David K. Summers, Charlotte Chilvers, Edwin R. Okkenhaug, Klaus Morris, Andrew Conway |
author_facet | Wood, Alexander J.T. Vassallo, Arlette M. Ruchaud-Sparagano, Marie-Hélène Scott, Jonathan Zinnato, Carmelo Gonzalez-Tejedo, Carmen Kishore, Kamal D’Santos, Clive S. Simpson, A. John Menon, David K. Summers, Charlotte Chilvers, Edwin R. Okkenhaug, Klaus Morris, Andrew Conway |
author_sort | Wood, Alexander J.T. |
collection | PubMed |
description | Critical illness is accompanied by the release of large amounts of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of neutrophils which is associated with adverse outcomes. The signaling pathways that mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy donor neutrophils exposed to purified C5a demonstrated a prolonged defect (7 hours) in phagocytosis of Staphylococcus aureus. Phosphoproteomic profiling of 2712 phosphoproteins identified persistent C5a signaling and selective impairment of phagosomal protein phosphorylation on exposure to S. aureus. Notable proteins included early endosomal marker ZFYVE16 and V-ATPase proton channel component ATPV1G1. An assay of phagosomal acidification demonstrated C5a-induced impairment of phagosomal acidification, which was recapitulated in neutrophils from critically ill patients. Examination of the C5a-impaired protein phosphorylation indicated a role for the PI3K VPS34 in phagosomal maturation. Inhibition of VPS34 impaired neutrophil phagosomal acidification and killing of S. aureus. This study provides a phosphoproteomic assessment of human neutrophil signaling in response to S. aureus and its disruption by C5a, identifying a defect in phagosomal maturation and mechanisms of immune failure in critical illness. |
format | Online Article Text |
id | pubmed-7455072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-74550722020-09-01 C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling Wood, Alexander J.T. Vassallo, Arlette M. Ruchaud-Sparagano, Marie-Hélène Scott, Jonathan Zinnato, Carmelo Gonzalez-Tejedo, Carmen Kishore, Kamal D’Santos, Clive S. Simpson, A. John Menon, David K. Summers, Charlotte Chilvers, Edwin R. Okkenhaug, Klaus Morris, Andrew Conway JCI Insight Research Article Critical illness is accompanied by the release of large amounts of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of neutrophils which is associated with adverse outcomes. The signaling pathways that mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy donor neutrophils exposed to purified C5a demonstrated a prolonged defect (7 hours) in phagocytosis of Staphylococcus aureus. Phosphoproteomic profiling of 2712 phosphoproteins identified persistent C5a signaling and selective impairment of phagosomal protein phosphorylation on exposure to S. aureus. Notable proteins included early endosomal marker ZFYVE16 and V-ATPase proton channel component ATPV1G1. An assay of phagosomal acidification demonstrated C5a-induced impairment of phagosomal acidification, which was recapitulated in neutrophils from critically ill patients. Examination of the C5a-impaired protein phosphorylation indicated a role for the PI3K VPS34 in phagosomal maturation. Inhibition of VPS34 impaired neutrophil phagosomal acidification and killing of S. aureus. This study provides a phosphoproteomic assessment of human neutrophil signaling in response to S. aureus and its disruption by C5a, identifying a defect in phagosomal maturation and mechanisms of immune failure in critical illness. American Society for Clinical Investigation 2020-08-06 /pmc/articles/PMC7455072/ /pubmed/32634128 http://dx.doi.org/10.1172/jci.insight.137029 Text en © 2020 Wood et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Wood, Alexander J.T. Vassallo, Arlette M. Ruchaud-Sparagano, Marie-Hélène Scott, Jonathan Zinnato, Carmelo Gonzalez-Tejedo, Carmen Kishore, Kamal D’Santos, Clive S. Simpson, A. John Menon, David K. Summers, Charlotte Chilvers, Edwin R. Okkenhaug, Klaus Morris, Andrew Conway C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling |
title | C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling |
title_full | C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling |
title_fullStr | C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling |
title_full_unstemmed | C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling |
title_short | C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling |
title_sort | c5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455072/ https://www.ncbi.nlm.nih.gov/pubmed/32634128 http://dx.doi.org/10.1172/jci.insight.137029 |
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