ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis
Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation...
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MDPI AG
2019-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/9/964 |
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| author | Izabela Galvão Rayssa M. Athayde Denise A. Perez Alesandra C. Reis Luisa Rezende Vivian Louise S. de Oliveira Barbara M. Rezende William A. Gonçalves Lirlândia P. Sousa Mauro M. Teixeira Vanessa Pinho |
| author_facet | Izabela Galvão Rayssa M. Athayde Denise A. Perez Alesandra C. Reis Luisa Rezende Vivian Louise S. de Oliveira Barbara M. Rezende William A. Gonçalves Lirlândia P. Sousa Mauro M. Teixeira Vanessa Pinho |
| author_sort | Izabela Galvão |
| collection | DOAJ |
| description | Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1β levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases. |
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| issn | 2073-4409 |
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| last_indexed | 2024-03-12T06:01:44Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-60f2caae9d6a4b20811bddb062dc88ce2023-09-03T04:05:22ZengMDPI AGCells2073-44092019-08-018996410.3390/cells8090964cells8090964ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil ApoptosisIzabela Galvão0Rayssa M. Athayde1Denise A. Perez2Alesandra C. Reis3Luisa Rezende4Vivian Louise S. de Oliveira5Barbara M. Rezende6William A. Gonçalves7Lirlândia P. Sousa8Mauro M. Teixeira9Vanessa Pinho10Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Enfermagem Básica, Escola de Enfermagem, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, BrazilDepartamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia; Universidade Federal de Minas Gerais, Belo Horizonte 312701-901, BrazilDepartamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilDepartamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, BrazilUncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1β levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases.https://www.mdpi.com/2073-4409/8/9/964acute inflammationneutrophilresolution of inflammationROCKapoptosisefferocytosis |
| spellingShingle | Izabela Galvão Rayssa M. Athayde Denise A. Perez Alesandra C. Reis Luisa Rezende Vivian Louise S. de Oliveira Barbara M. Rezende William A. Gonçalves Lirlândia P. Sousa Mauro M. Teixeira Vanessa Pinho ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis Cells acute inflammation neutrophil resolution of inflammation ROCK apoptosis efferocytosis |
| title | ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis |
| title_full | ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis |
| title_fullStr | ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis |
| title_full_unstemmed | ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis |
| title_short | ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis |
| title_sort | rock inhibition drives resolution of acute inflammation by enhancing neutrophil apoptosis |
| topic | acute inflammation neutrophil resolution of inflammation ROCK apoptosis efferocytosis |
| url | https://www.mdpi.com/2073-4409/8/9/964 |
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