Constitutive activation of the Src family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response

Ernst, M., Inglese, M., Scholz, G. M., Harder, K. W., Clay, F. J., Bozinovski, S., Waring, P., Darwiche, R., Kay, T., Sly, P., Collins, R., Turner, D., Hibbs, M. L., Anderson, G. P. and Dunn, A. R. (2002) Constitutive activation of the Src family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. Journal of Experimental Medicine, 196 5: 589-604. doi:10.1084/jem.20020873

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Author Ernst, M.
Inglese, M.
Scholz, G. M.
Harder, K. W.
Clay, F. J.
Bozinovski, S.
Waring, P.
Darwiche, R.
Kay, T.
Sly, P.
Collins, R.
Turner, D.
Hibbs, M. L.
Anderson, G. P.
Dunn, A. R.
Title Constitutive activation of the Src family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response
Journal name Journal of Experimental Medicine   Check publisher's open access policy
ISSN 0022-1007
1540-9538
Publication date 2002-09
Sub-type Article (original research)
DOI 10.1084/jem.20020873
Open Access Status File (Publisher version)
Volume 196
Issue 5
Start page 589
End page 604
Total pages 16
Place of publication New York, NY, United States
Publisher Rockefeller University Press
Language eng
Formatted abstract
To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated HckF/F "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y499-residue in the Hck protein. Unlike their Hck-/- "loss-of-function" counterparts, HckF/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 HckF/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), HckF/F mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, HckF/F mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from HckF/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 HckF/F mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.
Keyword Knock-in mutation
Lps
Endotoxemia
Macrophage
Neutrophil
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Faculty of Health and Behavioural Sciences -- Publications
 
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Created: Wed, 17 Nov 2010, 11:24:45 EST