A hallmark symptom of SLE is elevated autoantibodies, especially anti-dsDNA antibodies in multiple organs and tissues. Deficiency of Dnase1L3, a serum endonuclease, allows the accumulation of self-DNA leading to autoantibody generation. The source of Dnase1L3 is primarily expressed by macrophages and dendritic cells. Complete Dnase1L3 deficiency is known to promote the SLE phenotype, however, the dosage required to prevent disease onset is unknown. We hypothesize that macrophages provide sufficient Dnase1L3 expression to regulate autoantibody levels in the host’s system. We generated conditional, macrophage specific Dnase1L3 knockout mice to assess disease progression. We collected serum samples from 6–50 weeks of age and measured total IgG and anti-dsDNA levels by ELISA to develop a longitudinal analysis of autoantibody elevation. At sacrifice, we observed pathology and measured IgG deposition in the kidney and heart by immunofluorescence. We observed that the elimination of Dnase1L3 in macrophages increased anti-dsDNA antibodies in the conditional knockout mice. In addition, we observed minor abnormalities in the glomeruli size for the conditional knockout mice as compared to the wild type mice. Our results indicate that macrophages are capable of providing protection against the development of SLE.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease caused by environmental factors and loss of key proteins. One such protein is a serum endonuclease secreted by macrophages and dendritic cells, Dnase1L3. Loss of Dnase1L3 causes pediatric-onset lupus in humans is Dnase1L3. Reduction in Dnase1L3 activity occurs in adult-onset human SLE. However, the amount of Dnase1L3 necessary to prevent lupus onset, if the impact is continuous or requires a threshold, and which phenotypes are most impacted by Dnase1L3 remain unknown. To reduce Dnase1L3 protein levels, we developed a genetic mouse model with reduced Dnase1L3 activity by deletingDnase1L3from macrophages (cKO). Serum Dnase1L3 levels were reduced 67%, though Dnase1 activity remained constant. Sera were collected weekly from cKO and littermate controls until 50 weeks of age. Homogeneous and peripheral anti-nuclear antibodies were detected by immunofluorescence, consistent with anti-dsDNA antibodies. Total IgM, total IgG, and anti-dsDNA antibody levels increased in cKO mice with increasing age. In contrast to global Dnase1L3-/-mice, anti-dsDNA antibodies were not elevated until 30 weeks of age. The cKO mice had minimal kidney pathology, except for deposition of immune complexes and C3. Based on these findings, we conclude that an intermediate reduction in serum Dnase1L3 causes mild lupus phenotypes. This suggest that macrophage-derived DnaselL3 is critical to limiting lupus.