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p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair

Repair of damaged tissue requires the coordinated action of inflammatory and tissue-specific cells to restore homeostasis, but the underlying regulatory mechanisms are poorly understood. In this paper, we report new roles for MKP-1 (mitogen-activated protein kinase [MAPK] phosphatase-1) in controlli...

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Autores principales: Perdiguero, Eusebio, Sousa-Victor, Pedro, Ruiz-Bonilla, Vanessa, Jardí, Mercè, Caelles, Carme, Serrano, Antonio L., Muñoz-Cánoves, Pura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198158/
https://www.ncbi.nlm.nih.gov/pubmed/21987635
http://dx.doi.org/10.1083/jcb.201104053
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author Perdiguero, Eusebio
Sousa-Victor, Pedro
Ruiz-Bonilla, Vanessa
Jardí, Mercè
Caelles, Carme
Serrano, Antonio L.
Muñoz-Cánoves, Pura
author_facet Perdiguero, Eusebio
Sousa-Victor, Pedro
Ruiz-Bonilla, Vanessa
Jardí, Mercè
Caelles, Carme
Serrano, Antonio L.
Muñoz-Cánoves, Pura
author_sort Perdiguero, Eusebio
collection PubMed
description Repair of damaged tissue requires the coordinated action of inflammatory and tissue-specific cells to restore homeostasis, but the underlying regulatory mechanisms are poorly understood. In this paper, we report new roles for MKP-1 (mitogen-activated protein kinase [MAPK] phosphatase-1) in controlling macrophage phenotypic transitions necessary for appropriate muscle stem cell–dependent tissue repair. By restricting p38 MAPK activation, MKP-1 allows the early pro- to antiinflammatory macrophage transition and the later progression into a macrophage exhaustion-like state characterized by cytokine silencing, thereby permitting resolution of inflammation as tissue fully recovers. p38 hyperactivation in macrophages lacking MKP-1 induced the expression of microRNA-21 (miR-21), which in turn reduced PTEN (phosphatase and tensin homologue) levels, thereby extending AKT activation. In the absence of MKP-1, p38-induced AKT activity anticipated the acquisition of the antiinflammatory gene program and final cytokine silencing in macrophages, resulting in impaired tissue healing. Such defects were reversed by temporally controlled p38 inhibition. Conversely, miR-21–AKT interference altered homeostasis during tissue repair. This novel regulatory mechanism involving the appropriate balance of p38, MKP-1, miR-21, and AKT activities may have implications in chronic inflammatory degenerative diseases.
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spelling pubmed-31981582012-04-17 p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair Perdiguero, Eusebio Sousa-Victor, Pedro Ruiz-Bonilla, Vanessa Jardí, Mercè Caelles, Carme Serrano, Antonio L. Muñoz-Cánoves, Pura J Cell Biol Research Articles Repair of damaged tissue requires the coordinated action of inflammatory and tissue-specific cells to restore homeostasis, but the underlying regulatory mechanisms are poorly understood. In this paper, we report new roles for MKP-1 (mitogen-activated protein kinase [MAPK] phosphatase-1) in controlling macrophage phenotypic transitions necessary for appropriate muscle stem cell–dependent tissue repair. By restricting p38 MAPK activation, MKP-1 allows the early pro- to antiinflammatory macrophage transition and the later progression into a macrophage exhaustion-like state characterized by cytokine silencing, thereby permitting resolution of inflammation as tissue fully recovers. p38 hyperactivation in macrophages lacking MKP-1 induced the expression of microRNA-21 (miR-21), which in turn reduced PTEN (phosphatase and tensin homologue) levels, thereby extending AKT activation. In the absence of MKP-1, p38-induced AKT activity anticipated the acquisition of the antiinflammatory gene program and final cytokine silencing in macrophages, resulting in impaired tissue healing. Such defects were reversed by temporally controlled p38 inhibition. Conversely, miR-21–AKT interference altered homeostasis during tissue repair. This novel regulatory mechanism involving the appropriate balance of p38, MKP-1, miR-21, and AKT activities may have implications in chronic inflammatory degenerative diseases. The Rockefeller University Press 2011-10-17 /pmc/articles/PMC3198158/ /pubmed/21987635 http://dx.doi.org/10.1083/jcb.201104053 Text en © 2011 Perdiguero et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Perdiguero, Eusebio
Sousa-Victor, Pedro
Ruiz-Bonilla, Vanessa
Jardí, Mercè
Caelles, Carme
Serrano, Antonio L.
Muñoz-Cánoves, Pura
p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair
title p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair
title_full p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair
title_fullStr p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair
title_full_unstemmed p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair
title_short p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair
title_sort p38/mkp-1–regulated akt coordinates macrophage transitions and resolution of inflammation during tissue repair
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198158/
https://www.ncbi.nlm.nih.gov/pubmed/21987635
http://dx.doi.org/10.1083/jcb.201104053
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