Matthias Ernst,
Melissa Inglese, Glen M. Scholz,
Kenneth W. Harder,
Fiona J. Clay,
Steven Bozinovski,
Paul Waring,
Rima Darwiche,
Tom Kay,
Peter Sly,
Rachel Collins,
Debra Turner,
Margaret L. Hibbs,
Gary P. Anderson,
Ashley R. Dunn
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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.
Journal of Experimental Medicine 09/2002; 196(5):589-604. · 13.85 Impact Factor
