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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 [ 3 H]-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.

In Lysinuric Protein Intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages