In lysinuric protein intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages

Amelia Barilli, Bianca Maria Rotoli, Rossana Visigalli, Ovidio Bussolati, Gian C. Gazzola, Zamir Kadija, Giuseppe Rodi, Francesca Mariani, Maria Lorena Ruzza, Maurizio Luisetti, Valeria Dall'Asta

Research output: Contribution to journalArticle

Abstract

Background: In the recessive aminoaciduria Lysinuric Protein Intolerance (LPI), mutations of SLC7A7/y+LAT1 impair system y+L transport activity for cationic amino acids. A severe complication of LPI is a form of Pulmonary Alveolar Proteinosis (PAP), in which alveolar spaces are filled with lipoproteinaceous material because of the impaired surfactant clearance by resident macrophages. The pathogenesis of LPI-associated PAP remains still obscure. The present study investigates for the first time the expression and function of y+LAT1 in monocytes and macrophages isolated from a patient affected by LPI-associated PAP. A comparison with mesenchymal cells from the same subject has been also performed. Methods: Monocytes from peripheral blood were isolated from a 21-year-old patient with LPI. Alveolar macrophages and fibroblastic-like mesenchymal cells were obtained from a whole lung lavage (WLL) performed on the same patient. System y+L activity was determined measuring the 1-min uptake of [3H]-arginine under discriminating conditions. Gene expression was evaluated through qRT-PCR. Results: We have found that: 1) system y+L activity is markedly lowered in monocytes and alveolar macrophages from the LPI patient, because of the prevailing expression of SLC7A7/y+LAT1 in these cells; 2) on the contrary, fibroblasts isolated from the same patient do not display the transport defect due to compensation by the SLC7A6/y+LAT2 isoform; 3) in both normal and LPI monocytes, GM-CSF induces the expression of SLC7A7, suggesting that the gene is a target of the cytokine; 4) GM-CSF-induced differentiation of LPI monocytes is comparable to that of normal cells, demonstrating that GM-CSF signalling is unaltered; 5) general and respiratory conditions of the patient, along with PAP-associated parameters, markedly improved after GM-CSF therapy through aerosolization. Conclusions: Monocytes and macrophages, but not fibroblasts, derived from a LPI patient clearly display the defect in system y+L-mediated arginine transport. The different transport phenotypes are referable to the relative levels of expression of SLC7A7 and SLC7A6. Moreover, the expression of SLC7A7 is regulated by GM-CSF in monocytes, pointing to a role of y+LAT1 in the pathogenesis of LPI associated PAP.

Original languageEnglish
Article number32
JournalOrphanet Journal of Rare Diseases
Volume5
Issue number1
DOIs
Publication statusPublished - 2010

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Granulocyte-Macrophage Colony-Stimulating Factor
Monocytes
Macrophages
Pulmonary Alveolar Proteinosis
Alveolar Macrophages
Arginine
Fibroblasts
Lysinuric Protein Intolerance
Bronchoalveolar Lavage
Surface-Active Agents
Protein Isoforms
Cytokines
Phenotype
Gene Expression
Amino Acids
Polymerase Chain Reaction
Mutation

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Barilli, A., Rotoli, B. M., Visigalli, R., Bussolati, O., Gazzola, G. C., Kadija, Z., ... Dall'Asta, V. (2010). In lysinuric protein intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages. Orphanet Journal of Rare Diseases, 5(1), [32]. https://doi.org/10.1186/1750-1172-5-32

In lysinuric protein intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages. / Barilli, Amelia; Rotoli, Bianca Maria; Visigalli, Rossana; Bussolati, Ovidio; Gazzola, Gian C.; Kadija, Zamir; Rodi, Giuseppe; Mariani, Francesca; Ruzza, Maria Lorena; Luisetti, Maurizio; Dall'Asta, Valeria.

In: Orphanet Journal of Rare Diseases, Vol. 5, No. 1, 32, 2010.

Research output: Contribution to journalArticle

Barilli, A, Rotoli, BM, Visigalli, R, Bussolati, O, Gazzola, GC, Kadija, Z, Rodi, G, Mariani, F, Ruzza, ML, Luisetti, M & Dall'Asta, V 2010, 'In lysinuric protein intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages', Orphanet Journal of Rare Diseases, vol. 5, no. 1, 32. https://doi.org/10.1186/1750-1172-5-32
Barilli, Amelia ; Rotoli, Bianca Maria ; Visigalli, Rossana ; Bussolati, Ovidio ; Gazzola, Gian C. ; Kadija, Zamir ; Rodi, Giuseppe ; Mariani, Francesca ; Ruzza, Maria Lorena ; Luisetti, Maurizio ; Dall'Asta, Valeria. / In lysinuric protein intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages. In: Orphanet Journal of Rare Diseases. 2010 ; Vol. 5, No. 1.
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AU - Barilli, Amelia

AU - Rotoli, Bianca Maria

AU - Visigalli, Rossana

AU - Bussolati, Ovidio

AU - Gazzola, Gian C.

AU - Kadija, Zamir

AU - Rodi, Giuseppe

AU - Mariani, Francesca

AU - Ruzza, Maria Lorena

AU - Luisetti, Maurizio

AU - Dall'Asta, Valeria

PY - 2010

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N2 - Background: In the recessive aminoaciduria Lysinuric Protein Intolerance (LPI), mutations of SLC7A7/y+LAT1 impair system y+L transport activity for cationic amino acids. A severe complication of LPI is a form of Pulmonary Alveolar Proteinosis (PAP), in which alveolar spaces are filled with lipoproteinaceous material because of the impaired surfactant clearance by resident macrophages. The pathogenesis of LPI-associated PAP remains still obscure. The present study investigates for the first time the expression and function of y+LAT1 in monocytes and macrophages isolated from a patient affected by LPI-associated PAP. A comparison with mesenchymal cells from the same subject has been also performed. Methods: Monocytes from peripheral blood were isolated from a 21-year-old patient with LPI. Alveolar macrophages and fibroblastic-like mesenchymal cells were obtained from a whole lung lavage (WLL) performed on the same patient. System y+L activity was determined measuring the 1-min uptake of [3H]-arginine under discriminating conditions. Gene expression was evaluated through qRT-PCR. Results: We have found that: 1) system y+L activity is markedly lowered in monocytes and alveolar macrophages from the LPI patient, because of the prevailing expression of SLC7A7/y+LAT1 in these cells; 2) on the contrary, fibroblasts isolated from the same patient do not display the transport defect due to compensation by the SLC7A6/y+LAT2 isoform; 3) in both normal and LPI monocytes, GM-CSF induces the expression of SLC7A7, suggesting that the gene is a target of the cytokine; 4) GM-CSF-induced differentiation of LPI monocytes is comparable to that of normal cells, demonstrating that GM-CSF signalling is unaltered; 5) general and respiratory conditions of the patient, along with PAP-associated parameters, markedly improved after GM-CSF therapy through aerosolization. Conclusions: Monocytes and macrophages, but not fibroblasts, derived from a LPI patient clearly display the defect in system y+L-mediated arginine transport. The different transport phenotypes are referable to the relative levels of expression of SLC7A7 and SLC7A6. Moreover, the expression of SLC7A7 is regulated by GM-CSF in monocytes, pointing to a role of y+LAT1 in the pathogenesis of LPI associated PAP.

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