Fgr Deficiency Results in Defective Eosinophil Recruitment to the Lung During Allergic Airway Inflammation

Vicentini, L.; Mazzi, Paola; Caveggion, Elena; Continolo, Silvia; Fumagalli, Laura; Lapinet-Vera, José A.; Lowell, Clifford A.; Berton, Giorgio

doi:10.4049/jimmunol.168.12.6446

Cited by 27 publications

(16 citation statements)

References 57 publications

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“…However, in the LPS-induced systemic inflammatory reaction, hck Ϫ/Ϫ fgr Ϫ/Ϫ PMNs accumulate in the blood and are impaired in their capability to migrate into the liver (67). In addition, Fgr deficiency results in a marked reduction in the accumulation of eosinophils in the lung in a murine model of allergic asthma (68). Noteworthy, mice expressing a constitutively active form of Hck or with the selective granulocyte inactivation of the Src family kinase inhibitor C-terminal Src kinase (Csk) develop an exaggerated pulmonary inflammation (69,70).…”

Section: Discussionmentioning

confidence: 99%

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

Fumagalli

Zhang

Baruzzi

et al. 2007

The Journal of Immunology

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106

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The chemotactic peptide formyl-methionyl-leucyl-phenilalanine (fMLP) triggers intracellular protein tyrosine phosphorylation leading to neutrophil activation. Deficiency of the Src family kinases Hck and Fgr have previously been found to regulate fMLP-induced degranulation. In this study, we further investigate fMLP signaling in hck−/−fgr−/− neutrophils and find that they fail to activate a respiratory burst and display reduced F-actin polymerization in response to fMLP. Additionally, albeit migration of both hck−/−fgr−/− mouse neutrophils and human neutrophils incubated with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) through 3-μm pore size Transwells was normal, deficiency, or inhibition, of Src kinases resulted in a failure of neutrophils to migrate through 1-μm pore size Transwells. Among MAPKs, phosphorylation of ERK1/2 was not different, phosphorylation of p38 was only partially affected, and phosphorylation of JNK was markedly decreased in fMLP-stimulated hck−/−fgr−/− neutrophils and in human neutrophils incubated with PP2. An increase in intracellular Ca2+ concentration and phosphorylation of Akt/PKB occurred normally in fMLP-stimulated hck−/−fgr−/− neutrophils, indicating that activation of both phosphoinositide-specific phospholipase C and PI3K is independent of Hck and Fgr. In contrast, phosphorylation of the Rho/Rac guanine nucleotide exchange factor Vav1 and the Rac target p21-activated kinases were markedly reduced in both hck−/−fgr−/− neutrophils and human neutrophils incubated with a PP2. Consistent with these findings, PP2 inhibited Rac2 activation in human neutrophils. We suggest that Hck and Fgr act within a signaling pathway triggered by fMLP receptors that involves Vav1 and p21-activated kinases, leading to respiratory burst and F-actin polymerization.

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Section: Discussionmentioning

confidence: 99%

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

Fumagalli

Zhang

Baruzzi

et al. 2007

The Journal of Immunology

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106

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“…Hck and Fgr are also reported to have negative regulatory capabilities. Opsonic phagocytosis is elevated in Fgr Ϫ/Ϫ macrophages as a result of increased association of the phosphatase SHP-1 with an ITIM in the signal regulatory phosphatase binding protein (SIRP␣) receptor (48). Studies also point to a regulatory role for Hck and Fgr in neutrophil and dendritic cell chemokine signaling (55).…”

Section: Fig 5 Hckmentioning

confidence: 98%

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

Nelson

Metz

et al. 2009

Infect Immun

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Src family tyrosine kinases (SFKs) phosphorylate immunotyrosine activation motifs in the cytoplasmic tail of multiple immunoreceptors, leading to the initiation of cellular effector functions, such as phagocytosis, reactive oxygen species production, and cytokine production. SFKs also play important roles in regulating these responses through the activation of immunotyrosine inhibitory motif-containing inhibitory receptors. As myeloid cells preferentially express the SFKs Hck, Fgr, and Lyn, we questioned the role of these kinases in innate immune responses to Pneumocystis murina. Increased phosphorylation of Hck was readily detectable in alveolar macrophages after stimulation with P. murina. We further observed decreased phosphorylation of Lyn on its C-terminal inhibitory tyrosine in P. murina-stimulated alveolar macrophages, indicating that SFKs were activated in alveolar macrophages in response to P. murina. Mice deficient in Hck, Fgr, and Lyn exhibited augmented clearance 3 and 7 days after intratracheal administration of P. murina, which correlated with elevated levels of interleukin 1␤ (IL-1␤), IL-6, CXCL1/KC, CCL2/monocyte chemoattractant protein 1, and granulocyte colony-stimulating factor in lung homogenates and a dramatic increase in macrophage and neutrophil recruitment. Augmented P. murina clearance was also observed in Lyn ؊/؊ mice 3 days postchallenge, although the level was less than that observed in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice. A correlate to augmented clearance of P. murina in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice was a greater ability of alveolar macrophages from these mice to kill P. murina in vitro, suggesting that SFKs regulate the alveolar macrophage effector function against P. murina. Mice deficient in paired immunoglobulin receptor B (PIR-B), an inhibitory receptor activated by SFKs, did not exhibit enhanced inflammatory responsiveness to or clearance of P. murina. Our results suggest that SFKs regulate innate lung responses to P. murina in a PIR-B-independent manner.Although the advent of prophylactic therapy against Pneumocystis jirovecii alone or in combination with highly active antiretroviral therapy has reduced the incidence of pneumonia caused by this fungal pathogen, this infection remains the most prevalent opportunistic infection in individuals with AIDS (25). Furthermore, individuals receiving immunosuppressive therapies, such as individuals undergoing solid organ or hematopoietic cell transplantation, are a growing population susceptible to Pneumocystis pneumonia (34) (33). These observations warrant a more thorough examination of interactions between Pneumocystis and the host in order to define and develop new vaccine and immunotherapeutic approaches to treat Pneumocystis pneumonia.An intense area of research over the last decade is investigating how lung immune cells recognize and respond to inhaled pathogens, such as P. murina. After inhalation of P. murina into the lungs, one of the first interactions with the host is recognition by the alveolar macrophage. Our laboratory has prev...

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“…Fgr is most highly expressed by mature blood granulocytes and monocytes, as well as tissue macrophages. Although Fgr negatively regulates Fc␥ receptor-mediated phagocytosis in macrophages (19), it appears to play a positive role in integrin-or chemokine-mediated responses in macrophages (52), eosinophils (14,57), and neutrophils (38). Of particular interest, Fgr has been identified as a downstream target of PLD-derived phosphatidic acid in neutrophils stimulated with chemotactic peptide (50).…”

Section: Discussionmentioning

confidence: 99%

Activation of RBL-2H3 Mast Cells Is Dependent on Tyrosine Phosphorylation of Phospholipase D2 by Fyn and Fgr

Choi

Hiragun

Lee

et al. 2004

Molecular and Cellular Biology

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Both phospholipase D1 (PLD1) and PLD2 regulate degranulation when RBL-2H3 cells are stimulated via the immunoglobulin E receptor, FcRI. However, the activation mechanism for PLD2 is unclear. As reported here, PLD2 but not PLD1 is phosphorylated through the Src kinases, Fyn and Fgr, and this phosphorylation appears to regulate PLD2 activation and degranulation. For example, only hemagglutinin-tagged PLD2 was tyrosine phosphorylated in antigen-stimulated cells that had been made to express HA-PLD1 and HA-PLD2. This phosphorylation was blocked by a Src kinase inhibitor or by small interfering RNAs directed against Fyn and Fgr and was enhanced by overexpression of Fyn and Fgr but not by other Src kinases. The phosphorylation and activity of PLD2 were further enhanced by the tyrosine phosphatase inhibitor, Na 3 VO 4 . Mutation of PLD2 at tyrosines 11, 14, 165, or 470 partially impaired, and mutation of all tyrosines blocked, PLD2 phosphorylation and activation, although two of these mutations were detrimental to PLD2 function. PLD2 phosphorylation preceded degranulation, both events were equally sensitive to inhibition of Src kinase activity, and both were enhanced by coexpression of PLD2 and the Src kinases. The findings provide the first description of a mechanism for activation of PLD2 in a physiological setting and of a role for Fgr in FcRI-mediated signaling.

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Fgr Deficiency Results in Defective Eosinophil Recruitment to the Lung During Allergic Airway Inflammation

Cited by 27 publications

References 57 publications

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

Activation of RBL-2H3 Mast Cells Is Dependent on Tyrosine Phosphorylation of Phospholipase D2 by Fyn and Fgr

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