Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, United States.
Department of Cell Biology and Physiology, Virginia Tech, Blacksburg, VA 24061, United States.
J Leukoc Biol. 2023 Nov 24;114(6):547-556. doi: 10.1093/jleuko/qiad115.
Systemic lupus erythematosus (SLE) is an autoimmune disease caused by environmental factors and loss of key proteins, including the endonuclease Dnase1L3. Dnase1L3 absence causes pediatric-onset lupus in humans, while reduced activity occurs in adult-onset SLE. The amount of Dnase1L3 that prevents lupus remains unknown. To genetically reduce Dnase1L3 levels, we developed a mouse model lacking Dnase1L3 in macrophages (conditional knockout [cKO]). Serum Dnase1L3 levels were reduced 67%, though Dnase1 activity remained constant. Homogeneous and peripheral antinuclear antibodies were detected in the sera by immunofluorescence, consistent with anti-double-stranded DNA (anti-dsDNA) antibodies. Total immunoglobulin M, total immunoglobulin G, and anti-dsDNA antibody levels increased in cKO mice with age. The cKO mice developed anti-Dnase1L3 antibodies. In contrast to global Dnase1L3-/- mice, anti-dsDNA antibodies were not elevated early in life. The cKO mice had minimal kidney pathology. Therefore, we conclude that an intermediate reduction in serum Dnase1L3 causes mild lupus phenotypes, and macrophage-derived DnaselL3 helps limit lupus.
系统性红斑狼疮（SLE）是一种由环境因素和关键蛋白缺失引起的自身免疫性疾病，其中包括核酸内切酶 Dnase1L3。Dnase1L3 的缺失会导致人类幼年起病的狼疮，而其活性降低则与成人起病的 SLE 相关。导致狼疮的 Dnase1L3 量尚不清楚。为了从遗传学上降低 Dnase1L3 水平，我们开发了一种巨噬细胞中缺乏 Dnase1L3 的小鼠模型（条件性敲除[cKO]）。血清 Dnase1L3 水平降低了 67%，而 Dnase1 活性保持不变。免疫荧光检测到血清中存在均质和外周抗核抗体，与抗双链 DNA（抗-dsDNA）抗体一致。cKO 小鼠随年龄增长，总免疫球蛋白 M、总免疫球蛋白 G 和抗-dsDNA 抗体水平升高。cKO 小鼠产生了抗 Dnase1L3 抗体。与 Dnase1L3 全身性缺失的小鼠不同，抗-dsDNA 抗体在生命早期并未升高。cKO 小鼠的肾脏病理最小。因此，我们得出结论，血清 Dnase1L3 的中度降低会导致轻度狼疮表型，而巨噬细胞来源的 Dnase1L3 有助于限制狼疮。
