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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2020
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.
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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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