Cargando…
Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response
To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2002
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193996/ https://www.ncbi.nlm.nih.gov/pubmed/12208875 http://dx.doi.org/10.1084/jem.20020873 |
_version_ | 1782147601594843136 |
---|---|
author | Ernst, Matthias Inglese, Melissa Scholz, Glen M. Harder, Kenneth W. Clay, Fiona J. Bozinovski, Steven Waring, Paul Darwiche, Rima Kay, Tom Sly, Peter Collins, Rachel Turner, Debra Hibbs, Margaret L. Anderson, Gary P. Dunn, Ashley R. |
author_facet | Ernst, Matthias Inglese, Melissa Scholz, Glen M. Harder, Kenneth W. Clay, Fiona J. Bozinovski, Steven Waring, Paul Darwiche, Rima Kay, Tom Sly, Peter Collins, Rachel Turner, Debra Hibbs, Margaret L. Anderson, Gary P. Dunn, Ashley R. |
author_sort | Ernst, Matthias |
collection | PubMed |
description | To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(−/−) “loss-of-function” counterparts, Hck(F/F) “gain-of-function” mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck(F/F) mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, Hck(F/F) mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck(F/F) mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFα production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck(F/F) mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage. |
format | Text |
id | pubmed-2193996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2002 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21939962008-04-11 Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response Ernst, Matthias Inglese, Melissa Scholz, Glen M. Harder, Kenneth W. Clay, Fiona J. Bozinovski, Steven Waring, Paul Darwiche, Rima Kay, Tom Sly, Peter Collins, Rachel Turner, Debra Hibbs, Margaret L. Anderson, Gary P. Dunn, Ashley R. J Exp Med Article To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(−/−) “loss-of-function” counterparts, Hck(F/F) “gain-of-function” mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck(F/F) mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, Hck(F/F) mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck(F/F) mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFα production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck(F/F) mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage. The Rockefeller University Press 2002-09-02 /pmc/articles/PMC2193996/ /pubmed/12208875 http://dx.doi.org/10.1084/jem.20020873 Text en Copyright © 2002, The Rockefeller University Press 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 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Ernst, Matthias Inglese, Melissa Scholz, Glen M. Harder, Kenneth W. Clay, Fiona J. Bozinovski, Steven Waring, Paul Darwiche, Rima Kay, Tom Sly, Peter Collins, Rachel Turner, Debra Hibbs, Margaret L. Anderson, Gary P. Dunn, Ashley R. Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response |
title | Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response |
title_full | Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response |
title_fullStr | Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response |
title_full_unstemmed | Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response |
title_short | Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response |
title_sort | constitutive activation of the src family kinase hck results in spontaneous pulmonary inflammation and an enhanced innate immune response |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193996/ https://www.ncbi.nlm.nih.gov/pubmed/12208875 http://dx.doi.org/10.1084/jem.20020873 |
work_keys_str_mv | AT ernstmatthias constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT inglesemelissa constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT scholzglenm constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT harderkennethw constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT clayfionaj constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT bozinovskisteven constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT waringpaul constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT darwicherima constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT kaytom constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT slypeter constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT collinsrachel constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT turnerdebra constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT hibbsmargaretl constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT andersongaryp constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse AT dunnashleyr constitutiveactivationofthesrcfamilykinasehckresultsinspontaneouspulmonaryinflammationandanenhancedinnateimmuneresponse |