Impaired Lysosomal Maturation in Macrophages underlies Pathogenisis in Systemic Lupus Erythematosus Public Deposited

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  • March 20, 2019
  • Monteith, Andrew
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
  • Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis leading to autoimmune and inflammatory diseases. We identified that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation resulting in heightened ROS production and attenuated lysosomal acidification. This diminishes their ability 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 hours 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 underlying events promote the accumulation of nuclear antigens and activation innate sensors that drives IFNα production and heightened cell death. These data identify a novel defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus. Current therapeutics either broadly suppresses the immune system or target one pathogenic factor in SLE (BAFF, IFNα, B cells). Therefore, identifying the molecular mechanism preventing lysosomal maturation in lupus-prone macrophages could provide a targeted therapeutic addressing multiple SLE pathologies. We identified that heightened mTOR activation (mTORC1 and mTORC2) and chronic localization to the cell membrane impairs lysosomal maturation and underlies the accumulation of IgG-ICs on the membrane. Furthermore treatment with Torin1 and not Rapamycin restored degradation of IgG-ICs implicating that mTORC2 activity contributed to impaired lysosome maturation. In B6 MFs we found that regulation of the activity of mTORC2 allows cofilin to depolymerize actin filaments following phagocytic cup assembly. Actin depolymerization initiated a localized caspase cascade that lead to the activation of caspase-1 in an inflammasome-independent manner. Caspase-1 then cleaved Rab39a on the membrane of phagosomes containing IgG-ICs; a necessary step for lysosomal maturation. In lupus-prone MFs, heightened mTORC2 activity phosphorylates cofilin, which prevents actin depolymerization and the caspase cascade, thus leaving Rab39a uncleaved. As a result, the lysosome is unable to mature and degrade the phagocytosed IgG-ICs. These findings identify a novel signaling pathway regulating lysosomal maturation and an underlying defect in basic cellular function that can lead to immunological activation.
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  • In Copyright
  • Vilen, Barbara J.
  • Jacobson, Ken
  • Cook, Jean
  • Costello, Joeseph
  • Ed, Collins
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016

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