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(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.
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia. matthias.ernst@ludwig.edu.au
Matthias
M
Ernst
Melissa
M
Inglese
Glen M
GM
Scholz
Kenneth W
KW
Harder
Fiona J
FJ
Clay
Steven
S
Bozinovski
Paul
P
Waring
Rima
R
Darwiche
Tom
T
Kay
Peter
P
Sly
Rachel
R
Collins
Debra
D
Turner
Margaret L
ML
Hibbs
Gary P
GP
Anderson
Ashley R
AR
Dunn
D019943:Amino Acid Substitution; D000818:Animals; D002448:Cell Adhesion; D004789:Enzyme Activation; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000502:physiology; D010587:Phagocytosis; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck
D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck