title: The Src family kinases Hck, Fgr, and Lyn are critical for the generation of the in vivo inflammatory environment without a direct role in leukocyte recruitment.
abstract: Although Src family kinases participate in leukocyte function in vitro, such as integrin signal transduction, their role in inflammation in vivo is poorly understood. We show that Src family kinases play a critical role in myeloid cell-mediated in vivo inflammatory reactions. Mice lacking the Src family kinases Hck, Fgr, and Lyn in the hematopoietic compartment were completely protected from autoantibody-induced arthritis and skin blistering disease, as well as from the reverse passive Arthus reaction, with functional overlap between the three kinases. Though the overall phenotype resembled the leukocyte recruitment defect observed in β2 integrin-deficient (CD18(-/-)) mice, Hck(-/-)Fgr(-/-)Lyn(-/-) neutrophils and monocytes/macrophages had no cell-autonomous in vivo or in vitro migration defect. Instead, Src family kinases were required for the generation of the inflammatory environment in vivo and for the release of proinflammatory mediators from neutrophils and macrophages in vitro, likely due to their role in Fcγ receptor signal transduction. Our results suggest that infiltrating myeloid cells release proinflammatory chemokine, cytokine, and lipid mediators that attract further neutrophils and monocytes from the circulation in a CD18-dependent manner. Src family kinases are required for the generation of the inflammatory environment but not for the intrinsic migratory ability of myeloid cells.
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, and MTA-SE "Lendület" Lymphatic Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, 1094 Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Kovács
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, and MTA-SE "Lendület" Lymphatic Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, 1094 Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Németh
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, and MTA-SE "Lendület" Lymphatic Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, 1094 Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Jakus
authors.affiliation: Department of Dermatology, University Hospital Freiburg and BIOSS Centre for Biological Signalling Studies, 79104 Freiburg, Germany.
authors.forename: Cassian
authors.initials: C
authors.lastname: Sitaru
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, and MTA-SE "Lendület" Lymphatic Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, 1094 Budapest, Hungary.
authors.forename: Edina
authors.initials: E
authors.lastname: Simon
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Futosi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, and János Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, and János Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Botz
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, and János Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, and János Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
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: Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, and MTA-SE "Lendület" Lymphatic Physiology Research Group of the Hungarian Academy of Sciences and the Semmelweis University, 1094 Budapest, Hungary mocsai.attila@med.semmelweis-univ.hu.
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
mesh_terms: D000818:Animals; D001183:Arthus Reaction / Q000276:immunology; D002465:Cell Movement / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D007249:Inflammation / Q000378:metabolism*; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases