title: The Src-Family Kinases Hck and Fgr Regulate Early Lipopolysaccharide-Induced Myeloid Cell Recruitment into the Lung and Their Ability To Secrete Chemokines.
abstract: 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.
authors.affiliation: Section of General Pathology, Department of Pathology and Diagnostics, University of Verona, Verona, 37134, Italy; and.
authors.forename: Paola
authors.initials: P
authors.lastname: Mazzi
authors.affiliation: Section of General Pathology, Department of Pathology and Diagnostics, University of Verona, Verona, 37134, Italy; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Caveggion
authors.affiliation: Section of General Pathology, Department of Pathology and Diagnostics, University of Verona, Verona, 37134, Italy; and.
authors.forename: Josè A
authors.initials: JA
authors.lastname: Lapinet-Vera
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Section of General Pathology, Department of Pathology and Diagnostics, University of Verona, Verona, 37134, Italy; and giorgio.berton@univr.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Berton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology* / Q000378:metabolism; D000069439:Dasatinib / Q000276:immunology / Q000494:pharmacology; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D018925:Chemokines; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; D000069439:Dasatinib