The Src-Family Kinases Hck and Fgr Regulate Early Lipopolysaccharide-Induced Myeloid Cell Recruitment into the Lung and Their Ability To Secrete Chemokines

• Published in: The Journal of immunology (1950) 2015-09, Vol.195 (5), p.2383-2395
• Main Authors: Mazzi, Paola, Caveggion, Elena, Lapinet-Vera, Josè A, Lowell, Clifford A, Berton, Giorgio
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Chemokines - immunology; Chemokines - secretion; Dasatinib - immunology; Dasatinib - pharmacology; Immunohistochemistry; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Lung - immunology; Lung - metabolism; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells - drug effects; Myeloid Cells - immunology; Myeloid Cells - metabolism; Neutrophil Infiltration - drug effects; Neutrophil Infiltration - genetics; Neutrophil Infiltration - immunology; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - immunology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-hck - genetics; Proto-Oncogene Proteins c-hck - immunology; Proto-Oncogene Proteins c-hck - metabolism; src-Family Kinases - genetics; src-Family Kinases - immunology; src-Family Kinases - metabolism; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1402011

Myeloid leukocyte recruitment into the lung in response to environmental cues represents a key factor for the induction of lung damage. We report that Hck- and Fgr-deficient mice show a profound impairment in early recruitment of neutrophils and monocytes in response to bacterial LPS. The reduction in interstitial and airway neutrophil recruitment was not due to a cell-intrinsic migratory defect, because Hck- and Fgr-deficient neutrophils were attracted to the airways by the chemokine CXCL2 as wild type cells. However, early accumulation of chemokines and TNF-α in the airways was reduced in hck(-/-)fgr(-/-) mice. Considering that chemokine and TNF-α release into the airways was neutrophil independent, as suggested by a comparison between control and neutrophil-depleted mice, we examined LPS-induced chemokine secretion by neutrophils and macrophages in wild type and mutant cells. Notably, mutant neutrophils displayed a marked deficit in their capability to release the chemokines CXCL1, CXCL2, CCL3, and CCL4 and TNF-α in response to LPS. However, intracellular accumulation of these chemokines and TNF-α, as well as secretion of a wide array of cytokines, including IL-1α, IL-1β, IL-6, and IL-10, by hck(-/-)fgr(-/-) neutrophils was normal. Intriguingly, secretion of CXCL1, CXCL2, CCL2, CCL3, CCL4, RANTES, and TNF-α, but not IL-1α, IL-1β, IL-6, IL-10, and GM-CSF, was also markedly reduced in bone marrow-derived macrophages. Consistently, the Src kinase inhibitors PP2 and dasatinib reduced chemokine secretion by neutrophils and bone marrow-derived macrophages. These findings identify Src kinases as a critical regulator of chemokine secretion in myeloid leukocytes during lung inflammation.