Phenotypic Evaluation of TREX1 Null Mice as a Model for Lupus-Like Autoimmune Disease

Abstract TREX1 (DNase III) is the major mammalian 3’-5’ DNA exonuclease and thought to play a role in cell death genomic degradation. Dysfunction of Trex1 has been suggested activate immune response by self DNA, as null mice develop inflammatory myocarditis similar autoimmune cardiomyopathy produce type 1 IFN. D18N causes monogenic cutaneous form lupus called familial chilblain exhibits dysfunctioned dsDNA-degrading activity, providing link between dsDNA degradation nucleic acid-mediated diseases. Using CRISPR-Cas9, we generated −/−mouse knocking out exon 2 performed comprehensive phenotypic analyses evaluate loss function its potential application SLE research. Both female male showed dramatically increased post-wean morbidity significantly serum ALT, AST LDH levels, compared wildtype heterozygotes from 6 24 weeks age, indicating liver heart injuries. Pathohistological analysis infiltration liver, heart, spleen, kidney, lung skin among mice. Serum anti-dsDNA antibody levels were remained high 7 25 consistent with Trex1’s being exonuclease. Urine protein creatinine ratio was at 28 age In conclusion, −/−mice this work lupus-like responses multiple organs, an urgently needed tool study Trex1-mediated autoimmunity therapeutic treatments for lupus.