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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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Monteith AJ,Kang S,Scott E,Hillman K,Rajfur Z,Jacobson K,Costello MJ,Vilen BJ

doi

10.1073/pnas.1513943113

subject

Has Abstract

pub_date

2016-04-12 00:00:00

pages

E2142-51

issue

15

eissn

0027-8424

issn

1091-6490

pii

1513943113

journal_volume

113

pub_type

杂志文章

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