Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

2016
journal article
article
dc.abstract.enDefects 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 IFN alpha 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.pl
dc.affiliationWydział Fizyki, Astronomii i Informatyki Stosowanej : Instytut Fizyki im. Mariana Smoluchowskiegopl
dc.contributor.authorMonteith, Andrew J.pl
dc.contributor.authorKang, SunAhpl
dc.contributor.authorScott, Ericpl
dc.contributor.authorHillman, Kaipl
dc.contributor.authorRajfur, Zenon - 214965 pl
dc.contributor.authorJacobson, Kenpl
dc.contributor.authorCostello, Joseph M.pl
dc.contributor.authorVilen, Barbara J.pl
dc.date.accessioned2016-06-30T10:18:47Z
dc.date.available2016-06-30T10:18:47Z
dc.date.issued2016pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.number15pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume113pl
dc.identifier.articleidE2142-E2151pl
dc.identifier.doi10.1073/pnas.1513943113pl
dc.identifier.eissn1091-6490pl
dc.identifier.issn0027-8424pl
dc.identifier.urihttp://ruj.uj.edu.pl/xmlui/handle/item/28524
dc.languageengpl
dc.language.containerengpl
dc.rightsDodaję tylko opis bibliograficzny*
dc.rights.licenceOTHER
dc.rights.uri*
dc.share.typeinne
dc.subject.ensystemic lupus erythematosuspl
dc.subject.enFc gamma receptorspl
dc.subject.enlysosomal acidificationpl
dc.subject.enAIM2pl
dc.subject.enTRIM21pl
dc.subtypeArticlepl
dc.titleDefects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosuspl
dc.title.journalProceedings of the National Academy of Sciences of the United States of Americapl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
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 IFN alpha 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.
dc.affiliationpl
Wydział Fizyki, Astronomii i Informatyki Stosowanej : Instytut Fizyki im. Mariana Smoluchowskiego
dc.contributor.authorpl
Monteith, Andrew J.
dc.contributor.authorpl
Kang, SunAh
dc.contributor.authorpl
Scott, Eric
dc.contributor.authorpl
Hillman, Kai
dc.contributor.authorpl
Rajfur, Zenon - 214965
dc.contributor.authorpl
Jacobson, Ken
dc.contributor.authorpl
Costello, Joseph M.
dc.contributor.authorpl
Vilen, Barbara J.
dc.date.accessioned
2016-06-30T10:18:47Z
dc.date.available
2016-06-30T10:18:47Z
dc.date.issuedpl
2016
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.numberpl
15
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
113
dc.identifier.articleidpl
E2142-E2151
dc.identifier.doipl
10.1073/pnas.1513943113
dc.identifier.eissnpl
1091-6490
dc.identifier.issnpl
0027-8424
dc.identifier.uri
http://ruj.uj.edu.pl/xmlui/handle/item/28524
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Dodaję tylko opis bibliograficzny
dc.rights.licence
OTHER
dc.rights.uri*
dc.share.type
inne
dc.subject.enpl
systemic lupus erythematosus
dc.subject.enpl
Fc gamma receptors
dc.subject.enpl
lysosomal acidification
dc.subject.enpl
AIM2
dc.subject.enpl
TRIM21
dc.subtypepl
Article
dc.titlepl
Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus
dc.title.journalpl
Proceedings of the National Academy of Sciences of the United States of America
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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