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The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model

Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3Kγ and PI3Kδ are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated th...

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Autores principales: Galvão, Izabela, Queiroz-Junior, Celso Martins, de Oliveira, Vivian Louise Soares, Pinho, Vanessa, Hirsch, Emilio, Teixeira, Mauro Martins
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330337/
https://www.ncbi.nlm.nih.gov/pubmed/30666201
http://dx.doi.org/10.3389/fphar.2018.01505
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author Galvão, Izabela
Queiroz-Junior, Celso Martins
de Oliveira, Vivian Louise Soares
Pinho, Vanessa
Hirsch, Emilio
Teixeira, Mauro Martins
author_facet Galvão, Izabela
Queiroz-Junior, Celso Martins
de Oliveira, Vivian Louise Soares
Pinho, Vanessa
Hirsch, Emilio
Teixeira, Mauro Martins
author_sort Galvão, Izabela
collection PubMed
description Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3Kγ and PI3Kδ are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated the contribution of PI3Kγ and PI3Kδ to the resolution of inflammation in a model of gout in mice. Methods and Results: Experiments were performed in wild-type male C57/Bl6 mice. Selective inhibitors of PI3K-γ (AS605240) or PI3Kδ (GSK045) were injected in the joint 12 h after injection of MSU crystals, hence at the peak of inflammation. Inhibition of either PI3K isoform decreased number of neutrophils that migrated in response to the injection of MSU crystals. This was associated with reduction of myeloperoxidase activity and IL-1β levels in periarticular tissues and reduction of histological score. Joint dysfunction, as seen by reduced mechanical hypernociception, was improved by treatment with either inhibitor. The decrease in neutrophil numbers was associated with enhanced apoptosis and efferocytosis of these cells. There was shortening of resolution intervals, suggesting inhibition of either isoform induced the resolution of neutrophilic inflammation. Blockade of PI3Kγ or PI3Kδ reduced Nuclear Factor kappa B (NF-κB) activation. A pan-PI3K inhibitor (CL27c) reduced inflammation induced by MSU crystals by a magnitude that was similar to that attained by the PI3Kγ or PI3Kδ selective inhibitors alone. Conclusion: Taken together, these results suggest that neutrophils can use PI3Kγ or PI3Kδ to remain in the cavity and blockade of either isoenzyme is sufficient to induce their apoptosis and resolve inflammation in a murine model of gout.
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spelling pubmed-63303372019-01-21 The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model Galvão, Izabela Queiroz-Junior, Celso Martins de Oliveira, Vivian Louise Soares Pinho, Vanessa Hirsch, Emilio Teixeira, Mauro Martins Front Pharmacol Pharmacology Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3Kγ and PI3Kδ are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated the contribution of PI3Kγ and PI3Kδ to the resolution of inflammation in a model of gout in mice. Methods and Results: Experiments were performed in wild-type male C57/Bl6 mice. Selective inhibitors of PI3K-γ (AS605240) or PI3Kδ (GSK045) were injected in the joint 12 h after injection of MSU crystals, hence at the peak of inflammation. Inhibition of either PI3K isoform decreased number of neutrophils that migrated in response to the injection of MSU crystals. This was associated with reduction of myeloperoxidase activity and IL-1β levels in periarticular tissues and reduction of histological score. Joint dysfunction, as seen by reduced mechanical hypernociception, was improved by treatment with either inhibitor. The decrease in neutrophil numbers was associated with enhanced apoptosis and efferocytosis of these cells. There was shortening of resolution intervals, suggesting inhibition of either isoform induced the resolution of neutrophilic inflammation. Blockade of PI3Kγ or PI3Kδ reduced Nuclear Factor kappa B (NF-κB) activation. A pan-PI3K inhibitor (CL27c) reduced inflammation induced by MSU crystals by a magnitude that was similar to that attained by the PI3Kγ or PI3Kδ selective inhibitors alone. Conclusion: Taken together, these results suggest that neutrophils can use PI3Kγ or PI3Kδ to remain in the cavity and blockade of either isoenzyme is sufficient to induce their apoptosis and resolve inflammation in a murine model of gout. Frontiers Media S.A. 2019-01-07 /pmc/articles/PMC6330337/ /pubmed/30666201 http://dx.doi.org/10.3389/fphar.2018.01505 Text en Copyright © 2019 Galvão, Queiroz-Junior, de Oliveira, Pinho, Hirsch and Teixeira. http://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 Pharmacology
Galvão, Izabela
Queiroz-Junior, Celso Martins
de Oliveira, Vivian Louise Soares
Pinho, Vanessa
Hirsch, Emilio
Teixeira, Mauro Martins
The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model
title The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model
title_full The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model
title_fullStr The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model
title_full_unstemmed The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model
title_short The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model
title_sort inhibition of phosphoinositide-3 kinases induce resolution of inflammation in a gout model
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330337/
https://www.ncbi.nlm.nih.gov/pubmed/30666201
http://dx.doi.org/10.3389/fphar.2018.01505
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