Equilibrative Nucleoside Transporter 3 Deficiency Perturbs Lysosome Function and Macrophage Homeostasis

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Science  15 Dec 2011:
DOI: 10.1126/science.1213682


Lysosomal storage diseases (LSD) are a group of heterogeneous disorders caused by defects in lysosomal enzymes or transporters resulting in accumulation of undegraded macromolecules or metabolites. Macrophage numbers are expanded in several LSDs leading to histiocytosis of unknown pathophysiology. Here, we found that mice lacking the equilibrative nucleoside transporter 3 (ENT3) developed a spontaneous and progressive macrophage-dominated histiocytosis. In the absence of ENT3, defective apoptotic cell clearance lead to lysosomal nucleoside buildup, elevated intralysosomal pH, and altered macrophage function. The macrophage accumulation was partly due to elevated M-CSF/M-CSFR (macrophage-colony-stimulating-factor and receptor) expression and signaling secondary to the lysosomal defects. These studies suggest a cellular and molecular basis for the development of histiocytosis in several human syndromes associated with ENT3 mutations and potentially other LSDs.