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cGAS activation in classical dendritic cells causes autoimmunity in TREX1-deficient mice.

Authors :
Tong Li
Seoyun Yum
Junjiao Wu
Minghao Li
Yafang Deng
Lijun Sun
Xiaoxia Zuo
Chen, Zhijian J.
Source :
Proceedings of the National Academy of Sciences of the United States of America. 9/17/2024, Vol. 121 Issue 38, p1-8. 15p.
Publication Year :
2024

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
121
Issue :
38
Database :
Academic Search Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
180126832
Full Text :
https://doi.org/10.1073/pnas.2411747121