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

• Published in: The Journal of experimental medicine Vol. 196; no. 5; pp. 589 - 604
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 02.09.2002
• Subjects: Amino Acid Substitution; Animals; Cell Adhesion; Enzyme Activation; Lipopolysaccharides - toxicity; Lung - enzymology; Lung - immunology; Lung - pathology; Macrophages - drug effects; Macrophages - enzymology; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Monocytes - enzymology; Monocytes - immunology; Neutrophils - immunology; Neutrophils - physiology; Phagocytosis; Phenotype; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-hck
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20020873

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)alpha. 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 TNFalpha 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.