Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.
Graduate Program in Cell Biology and Regenerative Medicine, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, United States.
Front Immunol. 2022 Jun 13;13:882407. doi: 10.3389/fimmu.2022.882407. eCollection 2022.
The DNA-sensing cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) and mediates type-I interferon inflammatory responses to foreign viral and bacterial DNA as well as self-DNA. Studies of the intervertebral disc in humans and mice demonstrate associations between aging, increased cell senescence, and disc degeneration. Herein we assessed the role of STING in SASP promotion in STING gain- (N153S) and loss-of-function mouse models. N153S mice evidenced elevated circulating levels of proinflammatory markers including IL-1β, IL-6, and TNF-α, showed elevated monocyte and macrophage abundance in the vertebral marrow, and exhibited a mild trabecular and cortical bone phenotype in caudal vertebrae. Interestingly, despite systemic inflammation, the structural integrity of the disc and knee articular joint remained intact, and cells did not show a loss of their phenotype or elevated SASP. Transcriptomic analysis of N153S tissues demonstrated an upregulated immune response by disc cells, which did not closely resemble inflammatory changes in human tissues. Interestingly, STING mice also showed a mild vertebral bone phenotype, but the absence of STING did not reduce the abundance of SASP markers or improve the age-associated disc phenotype. Overall, the analyses of N153S and STING mice suggest that the cGAS-STING pathway is not a major contributor to SASP induction and consequent disc aging and degeneration but may play a minor role in the maintenance of trabecular bone in the vertebrae. This work contributes to a growing body of work demonstrating that systemic inflammation is not a key driver of disc degeneration.
DNA 感应 cGAS-STING 途径促进衰老相关分泌表型（SASP），并介导 I 型干扰素对外国病毒和细菌 DNA 以及自身 DNA 的炎症反应。人类和小鼠椎间盘的研究表明，衰老、细胞衰老增加和椎间盘退变之间存在关联。在此，我们评估了 STING 在 SASP 促进中的作用，分别在 STING 获得（N153S）和功能丧失小鼠模型中进行了评估。N153S 小鼠表现出循环中促炎标志物（包括 IL-1β、IL-6 和 TNF-α）水平升高，椎体骨髓中单核细胞和巨噬细胞丰度升高，并在尾骨表现出轻微的小梁和皮质骨表型。有趣的是，尽管存在全身炎症，但椎间盘和膝关节关节的结构完整性保持完整，细胞没有表现出其表型的丧失或 SASP 的升高。N153S 组织的转录组分析表明，椎间盘细胞的免疫反应上调，但这与人类组织中的炎症变化并不相似。有趣的是，STING 小鼠也表现出轻微的椎骨表型，但缺乏 STING 并不能减少 SASP 标志物的丰度或改善与年龄相关的椎间盘表型。总的来说，N153S 和 STING 小鼠的分析表明，cGAS-STING 途径不是 SASP 诱导和随后的椎间盘衰老和退变的主要原因，但可能在椎骨小梁骨的维持中发挥次要作用。这项工作有助于越来越多的工作表明，全身炎症不是椎间盘退变的关键驱动因素。
