cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model.
J Autoimmun. 2019 Mar 11;:
Authors: Xiao N, Wei J, Xu S, Du H, Huang M, Zhang S, Ye W, Sun L, Chen Q
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.
PMID: 30872080 [PubMed – as supplied by publisher]