Abstract 501: Anemia of Inflammation in an Exonuclease Deficient Lupus Mouse

Background: Patients with chronic inflammatory conditions, such as autoimmune diseases, infections, and cancer, often display anemia of inflammation (AI). 50% of patients with systemic lupus erythematosus display clinical signs of anemia. Mutations at aspartate residue 18 of the three prime repair exonuclease 1 ( TREX1 ) gene, which codes for the primary mammalian exonuclease, cause a monogenic form of cutaneous lupus erythematosus in humans and the genetically precise TREX1 D18N mice recapitulate a lupus-like disease. Objective: The link between failed DNA degradation during erythropoiesis and anemia prompted our studies to investigate whether TREX1 dysfunction might contribute to AI. Methods: AI in TREX1 D18N mice was determined through analysis of hematocrit, hemoglobin, gene expression analysis, immunohistochemistry (IHC) and flow cytometry. Response to phenylhydrazine (PHZ) induced anemia and activation of DNA sensing pathways were determined through IHC and interferon stimulatory gene (ISG) expression analysis of the liver, spleen and erythroblastic islands. Results: The TREX1 D18N mice exhibit altered erythropoiesis including reduced hematocrit, increased erythropoietic and hematotoxic gene expression levels in the spleen (~10-20 fold) and phenotypic signs of normocytic normochromic anemia. Anemia in TREX1 lupus mice is accompanied by increased erythropoietin (Epo) and extramedullary hematopoiesis. Furthermore, the TREX1 D18N mice display an inappropriate response to anemic challenge. Enhanced ISG expression is apparent and results from failed processing and sensing of undegraded erythroblast DNA. Conclusion: These results support a critical role for TREX1 in the degradation of erythroblast DNA and identify a distinct AI phenotype in TREX1 D18N mice.