title: Fgr deficiency results in defective eosinophil recruitment to the lung during allergic airway inflammation.
abstract: Using a mouse model of allergic lung inflammation, we found that mice deficient of Fgr, a Src family tyrosine kinase highly expressed in myelomonocytic cells, fail to develop lung eosinophilia in response to repeated challenge with aerosolized OVA. Both tissue and airway eosinophilia were markedly reduced in fgr(-/-) mice, whereas mice with the sole deficiency of Hck, another Src family member, responded normally. Release of allergic mediators, such as histamine, IL-4, RANTES/CCL5, and eotaxin/CCL11, in the airways of OVA-treated animals was equal in wild-type and fgr(-/-) mice. However, lung eosinophilia in Fgr-deficient mice correlated with a defective accumulation of GM-CSF and IL-5 in the airways, whereas secretion of these cytokines by spleen cells in response to OVA was normal. Examination of mRNA expression in whole lung tissue allowed us to detect comparable expression of transcripts for eotaxin/CCL11, macrophage-inflammatory protein-1 alpha/CCL3, macrophage-inflammatory protein-1 beta/CCL4, monocyte chemoattractant protein-1/CCL2, TCA-3/CCL1, IL-4, IL-10, IL-2, IL-3, IL-9, IL-15, and IFN-gamma in OVA-sensitized wild-type and fgr(-/-) mice. In contrast, the increase in IL-5 and IL-13 mRNA expression was lower in fgr(-/-) compared with wild-type mice. These findings suggest that deficiency of Fgr results in a marked reduction of lung eosinophilia and the establishment of a positive feedback loop based on autocrine secretion of eosinophil-active cytokines. These results identify Fgr as a novel pharmacological target to control allergic inflammation.
authors.affiliation: Department of Pathology, Section of General Pathology, University of Verona, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Vicentini
authors.forename: Paola
authors.initials: P
authors.lastname: Mazzi
authors.forename: Elena
authors.initials: E
authors.lastname: Caveggion
authors.forename: Silvia
authors.initials: S
authors.lastname: Continolo
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: José A
authors.initials: JA
authors.lastname: Lapinet-Vera
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Giorgio
authors.initials: G
authors.lastname: Berton
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics* / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000473:pathology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007274:Injections, Intraperitoneal; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051572:Proto-Oncogene Proteins c-hck; D012333:RNA, Messenger / Q000096:biosynthesis; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D018925:Chemokines; D016207:Cytokines; D015848:Interleukin-5; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases