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Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus
Neutrophil extracellular traps (NETs) serve to immobilize and kill pathogens, but also can contribute to the progression of several inflammatory and auto-immune diseases, as well as cancer. Whence the importance of elucidating the mechanisms underlying NET formation. In this regard, the PI3K signali...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9904237/ https://www.ncbi.nlm.nih.gov/pubmed/36761736 http://dx.doi.org/10.3389/fimmu.2023.1042686 |
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author | de Carvalho Oliveira, Vanessa Tatsiy, Olga McDonald, Patrick P. |
author_facet | de Carvalho Oliveira, Vanessa Tatsiy, Olga McDonald, Patrick P. |
author_sort | de Carvalho Oliveira, Vanessa |
collection | PubMed |
description | Neutrophil extracellular traps (NETs) serve to immobilize and kill pathogens, but also can contribute to the progression of several inflammatory and auto-immune diseases, as well as cancer. Whence the importance of elucidating the mechanisms underlying NET formation. In this regard, the PI3K signaling pathway has been shown to be crucial; yet little is known about which of its components are involved. Here, we identified the PI3K isoforms and associated signaling partners that are mobilized in response to different classes of physiological NET inducers (inflammatory cytokines, growth factors, chemoattractants). NET generation was assessed by microscopy and signalling molecule activation by immunoblot using phospho-antibodies. Across the various stimuli, PI3Kα and PI3Kγ isoforms clearly contributed to NET induction, while the participation of other isoforms was stimulus-dependent. Some PI3K isoforms were also found to signal through Akt, the canonical downstream effector of PI3K, while others did not. Downstream of PI3K, mTOR and PLCγ2 were used by all stimuli to control NET generation. Conversely, the involvement of other kinases depended on the stimulus – both TNFα and GM-CSF relied on PDK1 and Akt; and both TNFα and fMLP additionally used S6K. We further established that all PI3K isoforms and downstream effectors act belatedly in NET generation, as reported previously for PI3K. Finally, we revisited the PI3K-PDK1-Akt signaling hierarchy in human neutrophils and again found stimulus-dependent differences. Our data uncover unsuspected complexity and redundancy in the signaling machinery controlling NET formation through the all-important PI3K pathway. Conserved signaling molecules represent therapeutic targets for pathologies involving NETs and in this regard, the existence of drugs currently used in the clinic or undergoing clinical trials (which target PI3K isoforms, mTOR or Akt), underscores the translational potential of our findings. |
format | Online Article Text |
id | pubmed-9904237 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99042372023-02-08 Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus de Carvalho Oliveira, Vanessa Tatsiy, Olga McDonald, Patrick P. Front Immunol Immunology Neutrophil extracellular traps (NETs) serve to immobilize and kill pathogens, but also can contribute to the progression of several inflammatory and auto-immune diseases, as well as cancer. Whence the importance of elucidating the mechanisms underlying NET formation. In this regard, the PI3K signaling pathway has been shown to be crucial; yet little is known about which of its components are involved. Here, we identified the PI3K isoforms and associated signaling partners that are mobilized in response to different classes of physiological NET inducers (inflammatory cytokines, growth factors, chemoattractants). NET generation was assessed by microscopy and signalling molecule activation by immunoblot using phospho-antibodies. Across the various stimuli, PI3Kα and PI3Kγ isoforms clearly contributed to NET induction, while the participation of other isoforms was stimulus-dependent. Some PI3K isoforms were also found to signal through Akt, the canonical downstream effector of PI3K, while others did not. Downstream of PI3K, mTOR and PLCγ2 were used by all stimuli to control NET generation. Conversely, the involvement of other kinases depended on the stimulus – both TNFα and GM-CSF relied on PDK1 and Akt; and both TNFα and fMLP additionally used S6K. We further established that all PI3K isoforms and downstream effectors act belatedly in NET generation, as reported previously for PI3K. Finally, we revisited the PI3K-PDK1-Akt signaling hierarchy in human neutrophils and again found stimulus-dependent differences. Our data uncover unsuspected complexity and redundancy in the signaling machinery controlling NET formation through the all-important PI3K pathway. Conserved signaling molecules represent therapeutic targets for pathologies involving NETs and in this regard, the existence of drugs currently used in the clinic or undergoing clinical trials (which target PI3K isoforms, mTOR or Akt), underscores the translational potential of our findings. Frontiers Media S.A. 2023-01-24 /pmc/articles/PMC9904237/ /pubmed/36761736 http://dx.doi.org/10.3389/fimmu.2023.1042686 Text en Copyright © 2023 de Carvalho Oliveira, Tatsiy and McDonald 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 de Carvalho Oliveira, Vanessa Tatsiy, Olga McDonald, Patrick P. Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus |
title | Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus |
title_full | Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus |
title_fullStr | Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus |
title_full_unstemmed | Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus |
title_short | Phosphoinositol 3-kinase-driven NET formation involves different isoforms and signaling partners depending on the stimulus |
title_sort | phosphoinositol 3-kinase-driven net formation involves different isoforms and signaling partners depending on the stimulus |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9904237/ https://www.ncbi.nlm.nih.gov/pubmed/36761736 http://dx.doi.org/10.3389/fimmu.2023.1042686 |
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