Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Sorio, C; Montresor, A; Bolomini-Vittori, M; Caldrer, S; Rossi, B; Dusi, S; Angiari, S; Johansson, JE; Vezzalini, M; Leal, T; Calcaterra, E; Assael, BM; Melotti, P; Laudanna, C.
Mutations of Cystic Fibrosis Transmembrane Conductance Regulator Gene Cause a Monocyte-Selective Adhesion Deficiency.
Am J Respir Crit Care Med. 2016; 193(10): 1123-1133.
Doi: 10.1164/rccm.201510-1922OC
Web of Science
PubMed
FullText
FullText_MUG
- Co-authors Med Uni Graz
- Angiari Stefano
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- Cystic fibrosis (CF) is a common genetic disease caused by mutations of the cystic fibrosis 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 patients with CF 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. We evaluated whether CF leukocytes might present with alterations in cell adhesion and migration, a key process governing innate and acquired immune responses. We used ex vivo adhesion and chemotaxis assays, flow cytometry, immunofluorescence, and GTPase activity assays in this study. We found that chemoattractant-induced activation of β1 and β2 integrins and of chemotaxis is defective in mononuclear cells isolated from patients with CF. In contrast, polymorphonuclear leukocyte adhesion and chemotaxis were normal. The functionality of β1 and β2 integrins was restored by treatment of CF monocytes with the CFTR-correcting drugs VRT325 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. 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 into CF pathogenesis.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Cell Adhesion - genetics
- Cystic Fibrosis Transmembrane Conductance Regulator - genetics
- Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
- Disease Models, Animal -
- Flow Cytometry -
- Fluorescent Antibody Technique -
- Humans -
- Leukocytes - metabolism
- Male -
- Mice -
- Mice, Inbred C57BL -
- Monocytes - metabolism
- Mutation - genetics
- Find related publications in this database (Keywords)
- cell adhesion
- cystic fibrosis
- integrins
- leukocyte trafficking
- lung inflammation