Dnase1l3, short for Deoxyribonuclease 1 like 3, is a secreted enzyme. It plays a crucial role in digesting extracellular chromatin from apoptotic bodies, and is involved in the clearance of cell-free DNA, which is important for maintaining immune tolerance to self-DNA [1,4]. Its function is also linked to the regulation of autoimmune responses [3]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been valuable for studying Dnase1l3.

In KO/CKO mouse models, deficiency of Dnase1l3 in macrophages led to lupus-like phenotypes in mice, with increased levels of autoantibodies and a mild form of the disease, indicating that macrophage-derived DnaselL3 helps limit lupus [5]. In Dnase1 -/-Dnase1L3 -/- double-knockout mice, a dual-acting DNASE1/DNASE1L3 biologic was able to prevent the development of lupus, suggesting the importance of Dnase1l3 in the pathogenesis of lupus [2]. In colon cancer mouse models, Dnase1l3 deficiency in the tumor microenvironment enhanced tumor formation and growth, associated with impaired antitumor immunity [3].

In conclusion, Dnase1l3 is essential for immune tolerance through its role in extracellular chromatin digestion and cell-free DNA clearance. Mouse KO/CKO models have revealed its significance in autoimmune diseases like lupus and in cancer, specifically in modulating tumor growth and antitumor immunity. Understanding Dnase1l3's functions through these models provides insights into the mechanisms of these diseases and potential therapeutic strategies [1,2,3,5].

References:

1. Tusseau, Maud, Lovšin, Ema, Samaille, Charlotte, Cimaz, Rolando, Belot, Alexandre. 2022. DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling. In Journal of clinical immunology, 42, 1310-1320. doi:10.1007/s10875-022-01287-5. https://pubmed.ncbi.nlm.nih.gov/35670985/

2. Stabach, Paul R, Sims, Dominique, Gomez-Bañuelos, Eduardo, Andrade, Felipe, Braddock, Demetrios T. 2024. A dual-acting DNASE1/DNASE1L3 biologic prevents autoimmunity and death in genetic and induced lupus models. In JCI insight, 9, . doi:10.1172/jci.insight.177003. https://pubmed.ncbi.nlm.nih.gov/38888971/

3. Li, Wenling, Nakano, Hideki, Fan, Wei, Li, Xiaoling, Li, Leping. 2023. DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer. In JCI insight, 8, . doi:10.1172/jci.insight.168161. https://pubmed.ncbi.nlm.nih.gov/37581941/

4. Mathapathi, Samarth, Chu, Cong-Qiu. 2022. Contribution of Impaired DNASE1L3 Activity to Anti-DNA Autoantibody Production in Systemic Lupus Erythematosus. In Rheumatology and immunology research, 3, 17-22. doi:10.2478/rir-2022-0003. https://pubmed.ncbi.nlm.nih.gov/36467024/

5. Engavale, Minal, Hernandez, Colton J, Infante, Angelica, Sutton, R Bryan, Keyel, Peter A. . Deficiency of macrophage-derived Dnase1L3 causes lupus-like phenotypes in mice. In Journal of leukocyte biology, 114, 547-556. doi:10.1093/jleuko/qiad115. https://pubmed.ncbi.nlm.nih.gov/37804110/