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

• 成果类型: Article
• 署名作者: Li, Tong; Yum, Seoyun; Wu, Junjiao; Li, Minghao; Deng, Yafang; Sun, Lijun; Zuo, Xiaoxia; Chen, Zhijian J.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Central South University; Central South University; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14880
• DOI: 10.1073/pnas.2411747121
• 发表日期: 2024-09-17
• 关键词: cyclic gmp-amp; dna exonuclease trex1; lupus; gene; expression; mutations; synthase; disease; adapter; sensor

摘要

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-Gouti & egrave;res 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.