Dnase1l3-flox Mouse

Dnase1l3, or Deoxyribonuclease 1 like 3, is a secreted enzyme. Its main function is to digest extracellular chromatin from apoptotic bodies. It is involved in the process of cell-free DNA (cf.DNA) fragmentation, with cf.DNA first generated intracellularly involving Dnase1l3 and then further fragmented extracellularly by circulating Dnase1l3 [3]. Dnase1l3 is also crucial in regulating autoimmune responses to self-DNA and chromatin [2].

In mouse models, global Dnase1l3 knockout (KO) mice and macrophage-specific conditional knockout (CKO) mice have been studied. In macrophage-specific CKO mice, serum Dnase1l3 levels were reduced by 67%, and they developed lupus-like phenotypes, such as the presence of anti-double-stranded DNA (anti-dsDNA) antibodies, increased immunoglobulin levels, and anti-Dnase1l3 antibodies, though with minimal kidney pathology. This indicates that macrophage-derived Dnase1l3 helps limit lupus [4]. In Dnase1-/-Dnase1l3-/-double-knockout mice, a dual-acting Dnase1/Dnase1l3 biologic was able to prevent the development of lupus and rescue animals from death in a pristane-induced lupus model, suggesting a potential therapeutic approach for autoimmune diseases like systemic lupus erythematosus (SLE) [1]. In colon cancer mouse models, Dnase1l3 deficiency in the tumor microenvironment enhanced tumor formation and growth, associated with impaired antitumor immunity, highlighting its role in suppressing tumor progression [2].

In conclusion, Dnase1l3 is essential for DNA fragmentation and regulation of autoimmune responses. Mouse KO and CKO models have revealed its significant roles in autoimmune diseases like SLE and in tumor-related processes such as cancer development and antitumor immunity. These findings provide insights into potential therapeutic strategies for treating autoimmune diseases and cancer.