Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2022 Aug;43(8):2055-2066. doi: 10.1038/s41401-021-00813-2. Epub 2021 Dec 14.
Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1β, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.
急性肺损伤（ALI）是一种常见且具有破坏性的临床疾病，其特征是过度的炎症反应。干扰素基因刺激物（STING）是调节多种疾病中炎症和免疫反应的不可或缺分子，但 STING 在 ALI 发病机制中的作用尚未得到充分阐明。在这项研究中，我们探讨了 STING 调节脂多糖（LPS）诱导的肺损伤的分子机制。在 LPS 吸入诱导 ALI 之前，用 STING 抑制剂 C-176（15、30mg/kg，腹腔注射）预处理小鼠。结果显示，LPS 吸入显著增加了肺组织中 STING 的表达，而 C-176 预处理则呈剂量依赖性地抑制 STING 的表达，减少包括 TNF-α、IL-6、IL-12 和 IL-1β 在内的炎症细胞因子的产生，并抑制趋化因子和粘附分子血管细胞粘附蛋白-1（VCAM-1）在肺组织中的表达。同样，在 TNF-α刺激的 HMEC-1 细胞（常见和经典的血管内皮细胞）进行的体外实验表明，人 STING 抑制剂 H-151 或 STING siRNA 下调了 HMEC-1 细胞中粘附分子和趋化因子的表达水平，伴随着 TNF-α刺激时免疫细胞的粘附能力和趋化能力降低。我们进一步揭示，STING 抑制剂 H-151 或 STING 敲低显著降低了转录因子 STAT1 的磷酸化水平，进而影响其与趋化因子 CCL2 和粘附分子 VCAM-1 基因启动子的结合。综上所述，STING 抑制剂可通过防止血管内皮细胞介导的免疫细胞趋化和粘附来减轻 LPS 诱导的 ALI，表明 STING 可能是治疗 ALI 的有前途的治疗靶点。
