title: Equilibrative nucleoside transporter 3 deficiency perturbs lysosome function and macrophage homeostasis.
abstract: Lysosomal storage diseases (LSDs) 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 led to lysosomal nucleoside buildup, elevated intralysosomal pH, and altered macrophage function. The macrophage accumulation was partly due to increased 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.
authors.affiliation: Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Hsu
authors.forename: Weiyu
authors.initials: W
authors.lastname: Lin
authors.forename: Dhaya
authors.initials: D
authors.lastname: Seshasayee
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.forename: Eric
authors.initials: E
authors.lastname: Suto
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Huang
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Park
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Linda
authors.initials: L
authors.lastname: Rangell
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Lutman
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulufatu
authors.forename: Eric
authors.initials: E
authors.lastname: Stefanich
authors.forename: Cecile
authors.initials: C
authors.lastname: Chalouni
authors.forename: Meredith
authors.initials: M
authors.lastname: Sagolla
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.forename: Paul
authors.initials: P
authors.lastname: Fielder
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D049109:Cell Proliferation; D002478:Cells, Cultured; D015614:Histiocytosis / Q000503:physiopathology*; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology; D016464:Lysosomal Storage Diseases / Q000503:physiopathology; D008247:Lysosomes / Q000502:physiology* / Q000648:ultrastructure; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038042:Myelopoiesis; D033703:Nucleoside Transport Proteins / Q000235:genetics / Q000502:physiology*; D010587:Phagocytosis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction; D060168:Thymocytes / Q000276:immunology / Q000502:physiology
chemical_list: D000241:Adenosine; D016173:Macrophage Colony-Stimulating Factor; D033703:Nucleoside Transport Proteins; D016186:Receptor, Macrophage Colony-Stimulating Factor; C501425:Slc29a3 protein, mouse; C501424:SLC29A3 protein, human