Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
LMU Hospital Department of Medicine, Munich, Germany.
J Cell Mol Med. 2022 Oct;26(20):5267-5276. doi: 10.1111/jcmm.17556. Epub 2022 Sep 13.
Hypercholesterolemia exacerbates autoimmune response and accelerates the progression of several autoimmune disorders, but the mechanistic basis is not well understood. We recently demonstrated that hypercholesterolemia is associated with increased serum extracellular DNA levels secondary to a defect in DNase-mediated clearance of DNA. In this study, we tested whether the impaired DNase response plays a causal role in enhancing anti-nuclear antibody levels and renal immune complex deposition in an Apoe mouse model of hypercholesterolemia. We demonstrate that hypercholesterolemic mice have enhanced anti-ds-DNA and anti-nucleosome antibody levels which is associated with increased immune complex deposition in the renal glomerulus. Importantly, treatment with DNase1 led to a decrease in both the autoantibody levels as well as renal pathology. Additionally, we show that humans with hypercholesterolemia have decreased systemic DNase activity and increased anti-nuclear antibodies. In this context, our data suggest that recombinant DNase1 may be an attractive therapeutic strategy to lower autoimmune response and disease progression in patients with autoimmune disorders associated with concomitant hypercholesterolemia.
高胆固醇血症可加重自身免疫反应，并加速多种自身免疫性疾病的进展，但其中的机制尚不清楚。我们最近的研究表明，高胆固醇血症与血清细胞外 DNA 水平升高有关，这是由于 DNA 酶介导的 DNA 清除缺陷所致。在这项研究中，我们检测了受损的 DNA 酶反应是否在增强载脂蛋白 E 基因敲除小鼠模型的高胆固醇血症中的抗核抗体水平和肾脏免疫复合物沉积中起因果作用。我们发现，高胆固醇血症小鼠具有增强的抗双链 DNA 和抗核小体抗体水平，这与肾小球中免疫复合物沉积增加有关。重要的是，用 DNA 酶 1 治疗可降低自身抗体水平和肾脏病理。此外，我们还发现高胆固醇血症患者的全身 DNA 酶活性降低，抗核抗体增加。在这种情况下，我们的数据表明，重组 DNA 酶 1 可能是一种有吸引力的治疗策略，可降低与高胆固醇血症相关的自身免疫性疾病患者的自身免疫反应和疾病进展。
