Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States.
Merck & Co., Inc., Kenilworth, NJ, United States.
Front Immunol. 2021 Mar 29;12:605930. doi: 10.3389/fimmu.2021.605930. eCollection 2021.
Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASFas mice on a pure MRL/Fas background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.
DNA 的检测是宿主防御的重要决定因素，但也是自身炎症性和自身免疫性疾病的驱动因素。在缺乏 DNAseII 或 III（TREX1）的小鼠中，如果不能降解自身 DNA，会导致 cGAS-STING 途径的激活。在这些模型中，cGAS 或 STING 的缺失可改善疾病表现。然而，cGAS-STING 途径相对于内体 TLRs 在系统性红斑狼疮 (SLE) 中的作用仍存在争议。事实上，STING 缺陷未能挽救 Fas 缺陷的 SLE 易感小鼠的疾病表现，反而使其恶化。我们现在将这些观察结果扩展到通过腹腔注射 TMPD（角鲨烷）诱导的慢性 SLE 模型。我们发现，cGAS 和 STING 的缺失不仅未能使小鼠免受 TMPD 诱导的 SLE 影响，反而导致与 cGAS STING 充足的小鼠相比，自身抗体产生增加和蛋白尿水平升高。此外，我们使用 Crispr/Cas9 在纯 MRL/Fas 背景下生成了 cGASFas 小鼠，发现疾病略有加重，而不是减轻。我们假设 cGAS-STING 途径限制了 TLR 的激活，从而限制了这两种模型中的自身免疫表现。与这一前提一致，与 cGAS 或 STING 单敲除动物相比，缺乏 cGAS 和 Unc93B1 或 STING 和 Unc93B1 的小鼠表现出最小的全身性自身免疫。然而，在 B6 小鼠中，AAV 递送 DNAse I 可消除 TMPD 驱动的狼疮，这表明 DNA 是一个触发因素。总的来说，这项研究表明，cGAS-STING 途径在 SLE 的小鼠模型中不会促进全身性自身免疫。这些数据对于正在开发用于治疗全身性自身免疫的 cGAS-STING 靶向治疗具有重要意义。
