Alterations of arginine in Lysinuric Protein Intolerance (LPI) macrophages

Lysinuric Protein Intolerance (LPI) is an inherited transport defect of cationic amino acids (arginine, lysine and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells caused by mutations in SLC7A7 encoding for System y+L-related y+LAT1 protein. The severe clinical course of this disorder suggests that LPI should be considered a severe multisystem disease with features proper of 'metabolic' disorders. In particular, immune dysfunction could be attributed to an altered metabolism of nitric oxide (NO) secondary to abnormal arginine intracellular metabolism. To address this hypothesis we measured arginine transport/metabolism in monocyte-derived macrophages (MDM), obtained from peripheral blood monocytes isolated from 5 LPI patients. In these cells the efflux of 3H-arginine through System y+L was markedly lower than in normal MDM, with a decrease that ranged from 60 to 75%. Moreover, SLC7A7 silencing in a human monocytic cell line (THP-1 cells) caused a significant increase of intracellular arginine content. These results indicate that arginine entrapping takes place in LPI monocytes-macrophages, supporting the hypothesis that NO overproduction observed in vivo may be due to an abnormal intracellular metabolism of arginine. Supported by CLIMB (Children living with inherited metabolic diseases, Crewe, UK)