Abstract
BackgroundIn 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.MethodsMonocytes 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.ResultsWe 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.ConclusionsMonocytes 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.
Highlights
In the recessive aminoaciduria Lysinuric Protein Intolerance (LPI), mutations of SLC7A7/y+LAT1 impair system y+L transport activity for cationic amino acids
The defect affects transport system y+L, a member of the large group of heterodimeric amino acid transporters formed by a light subunit, which may be either y+LAT1 or y+LAT2 (SLC7A6 gene), and a glycoprotein (4F2 hc/CD98 hc) that is necessary for the correct expression of the transporter in the plasma membrane [2]
In the eighth month of life the baby was diagnosed as affected by LPI and, at the age of 15, a Pulmonary Alveolar Proteinosis (PAP) was diagnosed based on Computed Tomography (CT) scan of a crazy paving pattern and of a mild restrictive ventilatory impairment
Summary
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 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. Lysinuric Protein Intolerance (LPI, MIM 222700) is an autosomic, recessive, hyperdibasic aminoaciduria caused by defective cationic amino acid (CAA; L-arginine, L-lysine, L-ornithine) transport at the basolateral membrane of epithelial cells in the intestine and kidney [1]. Because of the transport defect, LPI patients have high renal clearance and low intestinal absorption of CAA and, as a consequence, their CAA plasma levels are usually low [5]. Pulmonary manifestations are variable and range from subclinical interstitial lung disease to severe complications, eventually leading to fatal Pulmonary Alveolar Proteinosis [7,8,9]
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