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

J Autoimmun. 2019 Jun;100:84-94. doi: 10.1016/j.jaut.2019.03.001. Epub 2019 Mar 11.

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.

Keywords: Autoimmune disorder; DNA sensor; IFN-signature; Innate immunity; Lupus; Trex1 mutation; cGAS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Autoimmune Diseases of the Nervous System* / genetics
  • Autoimmune Diseases of the Nervous System* / immunology
  • Autoimmune Diseases of the Nervous System* / pathology
  • Disease Models, Animal
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Exodeoxyribonucleases* / genetics
  • Exodeoxyribonucleases* / immunology
  • Humans
  • Lupus Erythematosus, Systemic* / genetics
  • Lupus Erythematosus, Systemic* / immunology
  • Lupus Erythematosus, Systemic* / pathology
  • Lymphocyte Activation*
  • Mice
  • Mice, Mutant Strains
  • Mutation, Missense*
  • Nervous System Malformations* / genetics
  • Nervous System Malformations* / immunology
  • Nervous System Malformations* / pathology
  • Nucleotidyltransferases* / genetics
  • Nucleotidyltransferases* / immunology
  • Phosphoproteins* / genetics
  • Phosphoproteins* / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • Phosphoproteins
  • Nucleotidyltransferases
  • cGAS protein, mouse
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1

Supplementary concepts

  • Aicardi-Goutieres syndrome