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Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response

Matthias Ernst¹, Melissa Inglese¹, Glen M. Scholz¹, Kenneth W. Harder¹, Fiona J. Clay¹, Steven Bozinovski³, Paul Waring⁴, Rima Darwiche², Tom Kay², Peter Sly⁵, Rachel Collins⁵, Debra Turner⁵, Margaret L. Hibbs¹, Gary P. Anderson³ and Ashley R. Dunn¹

¹ Ludwig Institute for Cancer Research, Royal Melbourne Hospital
² The Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital
³ Departments of Medicine and Pharmacology, University of Melbourne, Victoria 3050, Australia
⁴ Department of Pathology, Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002, Australia
⁵ Centre for Child Health Research, University of Western Australia, Perth, WA 6872, Australia

Address correspondence to M. Ernst, Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Victoria 3050, Australia. Phone: 61-3-3941-3149; Fax: 61-3-9341-3191. E-mail: matthias.ernst{at}ludwig.edu.au

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 Y₄₉₉-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). 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 TNF 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.

Key Words: knock-in mutation • LPS • endotoxemia • macrophage • neutrophil

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