Deletion of Dnase1L3 from Macrophages results in reduced serum Dnase activity in mice

Abstract

Dnase1L3 deficiency leads to 100% penetrance of pediatric onset Systemic lupus erythematous (SLE) while reduce Dnase1L3 levels is seen in adult-onset. Dnase1L3 is an endonuclease primarily secreted by myeloid cells like macrophages into the serum, where it degrades apoptotic bodies and chromatin, which reduces auto antibody formation and prevents SLE in both humans and mice. Importantly, reduction in the Dnase1L3 protein levels occurs both in adult-onset SLE in humans, and in polygenic murine models. This suggests that different levels of Dnase1L3 contribute to SLE progression. Also, decreasing Dnase1L3 levels leads to progressively worse SLE. However, the amount of serum Dnase1L3 needed, or whether the impact of Dnase1L3 is analog or digital remains unknown. In order to reduce Dnase1L3 protein levels, we generated Dnase1L3fl/fl x LysM-cre+/− conditional knockout (cKO) mice on B6 background. We determined the contribution of macrophage Dnase1L3 by measuring the Dnase1L3 protein levels and enzymatic activity by Dnase activity assay. We found that cKO mice showed ~2-log reduction in the serum Dnase activity. These cKO mice represent a cell-specific model to study the impact of Dnase1L3 protein levels on SLE pathogenesis. Together these findings suggest that macrophage specific Dnase1L3 may be a key player in lupus, however there could be other nucleases involved which we plan to inhibit using certain specific inhibitors. Overall, our findings suggest that macrophage specific Dnase1L3 is critical to prevent autoantibody formation in protecting lupus onset