cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model

Nanyang Xiao, Jingjing Wei, Shan Xu, Hekang Du, Miaohui Huang, Sitong Zhang, Weiwei Ye, Lijun Sun, Qi Chen

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi–Goutieres Syndrome (AGS)and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1D18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1D18N/D18N mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.

Original languageEnglish (US)
Pages (from-to)84-94
Number of pages11
JournalJournal of Autoimmunity
Volume100
DOIs
StatePublished - Jun 2019

Keywords

  • Autoimmune disorder
  • DNA sensor
  • IFN-signature
  • Innate immunity
  • Lupus
  • Trex1 mutation
  • cGAS

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Xiao, N., Wei, J., Xu, S., Du, H., Huang, M., Zhang, S., Ye, W., Sun, L., & Chen, Q. (2019). cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model. Journal of Autoimmunity, 100, 84-94. https://doi.org/10.1016/j.jaut.2019.03.001