Mutations of Cystic Fibrosis Transmembrane Conductance Regulator Gene Cause a Monocyte-Selective Adhesion Deficiency
| Autor: | Matteo Bolomini-Vittori, Baroukh M. Assael, Silvia Dusi, Alessio Montresor, Paola Melotti, Stefano Angiari, Carlo Laudanna, Marzia Vezzalini, Elisa Calcaterra, Teresinha Leal, Sara Caldrer, Claudio Sorio, Jan Evert Johansson, Barbara Rossi |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Integrins Cystic Fibrosis Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] Integrin Inflammation Biology Critical Care and Intensive Care Medicine Cystic fibrosis 03 medical and health sciences medicine Cell Adhesion Respiratory function Cell adhesion Monocyte Chemotaxis respiratory system medicine.disease Leukocyte Trafficking Cystic fibrosis transmembrane conductance regulator 030104 developmental biology medicine.anatomical_structure Immunology biology.protein medicine.symptom |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine, 193, 10, pp. 1123-33 American Journal of Respiratory and Critical Care Medicine, 193, 1123-33 |
| ISSN: | 1073-449X |
| Popis: | Item does not contain fulltext BACKGROUND: Cystic fibrosis (CF) is a common genetic disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. Persistent lung inflammation, characterized by increasing polymorphonuclear leukocyte recruitment, is a major cause of the decline in respiratory function in CF patients, and is a leading cause of morbidity and mortality. CFTR is expressed in various cell types, including leukocytes, but its involvement in the regulation of leukocyte recruitment is unknown. METHODS: Ex vivo adhesion and chemotaxis, flow cytometry, immunofluorescence, GTPases activity assays. RESULTS: We found that chemoattractant-induced activation of beta1 and beta2 integrins and of chemotaxis is defective in mononuclear cells isolated from CF patients. In contrast, polymorphonuclear leukocyte adhesion and chemotaxis were normal. The functionality of beta1 and beta2 integrins was restored by treatment of CF monocytes with the CFTR correcting drugs VX325 and VX809. Moreover, treatment of healthy monocytes with the CFTR inhibitor CFTR inh-172 blocked integrin activation by chemoattractants. In a murine model of lung inflammation, we found that integrin-independent migration of CF monocytes into the lung parenchyma was normal, whereas, in contrast, integrin-dependent transmigration into the alveolar space was impaired. Finally, signal transduction analysis showed that in CF monocytes chemoattractant-triggered activation of RhoA and CDC42 rho small GTPases, controlling integrin activation and chemotaxis respectively, was strongly deficient. CONCLUSION: Altogether, these data highlight the critical regulatory role of CFTR in integrin activation by chemoattractants in monocytes and identify CF as a new, cell-type selective, leukocyte adhesion deficiency disease providing new insights on CF pathogenesis. |
| Databáze: | OpenAIRE |
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