title: Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus.
abstract: Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG-immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization. Diminished degradation of IgG-ICs prolongs the intracellular residency of nucleic acids, leading to the activation of Toll-like receptors. It also promotes phagosomal membrane permeabilization, allowing dsDNA and IgG to leak into the cytosol and activate AIM2 and TRIM21. Collectively, these events promote the accumulation of nuclear antigens and activate innate sensors that drive IFNα production and heightened cell death. These data identify a previously unidentified defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus.
authors.affiliation: Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, NC 27599; Curriculum in Biochemistry & Biophysics, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Monteith
authors.affiliation: Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: SunAh
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.affiliation: Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Kai
authors.initials: K
authors.lastname: Hillman
authors.affiliation: Department of Cell Biology & Physiology, University of North Carolina, Chapel Hill, NC 27599; Department of Physics, Astronomy, and Applied Computer Science, Institute of Physics, Jagiellonian University, 31-007, Krakow, Poland;
authors.forename: Zenon
authors.initials: Z
authors.lastname: Rajfur
authors.affiliation: Department of Cell Biology & Physiology, University of North Carolina, Chapel Hill, NC 27599; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Ken
authors.initials: K
authors.lastname: Jacobson
authors.affiliation: Department of Cell Biology & Physiology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: M Joseph
authors.initials: MJ
authors.lastname: Costello
authors.affiliation: Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, NC 27599; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 barb_vilen@med.unc.edu.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Vilen
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D002463:Cell Membrane Permeability; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D006241:Haptens; D006433:Hemocyanins / Q000276:immunology; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012261:Ribonucleoproteins / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D000099207:SS-A Antigen
chemical_list: D000936:Antigen-Antibody Complex; D004247:DNA; D004268:DNA-Binding Proteins; D006241:Haptens; D006433:Hemocyanins; D007074:Immunoglobulin G; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D012261:Ribonucleoproteins; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D000099207:SS-A Antigen; C540422:Aim2 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; C054401:trinitrophenyl keyhole limpet hemocyanin
keywords: AIM2; Fc gamma receptors; TRIM21; lysosomal acidification; systemic lupus erythematosus