cGAS activation in classical dendritic cells causes autoimmunity in TREX1-deficient mice.
Proc Natl Acad Sci U S A
; 121(38): e2411747121, 2024 Sep 17.
Article
em En
| MEDLINE
| ID: mdl-39254994
ABSTRACT
Detection of cytosolic DNA by the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway provides immune defense against pathogens and cancer but can also cause autoimmunity when overactivated. The exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA in the cytosol and prevents cGAS activation by self-DNA. Loss-of-function mutations of the TREX1 gene are linked to autoimmune diseases such as Aicardi-Goutières syndrome, and mice deficient in TREX1 develop lethal inflammation in a cGAS-dependent manner. In order to determine the type of cells in which cGAS activation drives autoinflammation, we generated conditional cGAS knockout mice on the Trex1-/- background. Here, we show that genetic ablation of the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1-/- mice from all observed disease phenotypes including lethality, T cell activation, tissue inflammation, and production of antinuclear antibodies and interferon-stimulated genes. These results show that cGAS activation in cDC causes autoinflammation in response to self-DNA accumulated in the absence of TREX1.
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MEDLINE
Assunto principal:
Fosfoproteínas
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Células Dendríticas
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Autoimunidade
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Camundongos Knockout
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Exodesoxirribonucleases
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Nucleotidiltransferases
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article