Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo namesti 2, Prague 16000, Czech Republic.
Faculty of Science, Charles University, Albertov 6, Prague 12800, Czech Republic.
ACS Infect Dis. 2022 Mar 11;8(3):463-471. doi: 10.1021/acsinfecdis.1c00554. Epub 2022 Feb 8.
The cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway plays a crucial role in inducing an antiviral and antitumor immune response. We studied the effects of synthetic STING agonists on several immune populations and related cytokine production. In comparison with the toll-like receptor 7 (TLR7) agonist, STING agonists induced secretion of a broader proinflammatory cytokine spectrum. Unlike the TLR7 agonist, the structurally diverse STING agonists partially depleted B and NK cells and completely depleted CD14+ monocytes via induction of apoptosis. The TANK-binding kinase 1 inhibitor efficiently prevented interferon alpha (IFNα) secretion and cell depletion, suggesting their possible dependence on the cGAS-STING pathway activation. Finally, IFNα, tumor necrosis factor alpha, interleukin 6, and interleukin 1 beta secretion and CD14+ monocyte apoptosis were primary responses to STING agonists, whereas IFNγ was secreted secondarily. These findings bring new insights into the cGAS-STING pathway immunomodulation that is of future therapeutic importance.
cGAS-STING（环鸟苷酸-腺苷酸合酶-干扰素基因刺激物）途径在诱导抗病毒和抗肿瘤免疫反应中起着至关重要的作用。我们研究了合成 STING 激动剂对几种免疫群体和相关细胞因子产生的影响。与 Toll 样受体 7（TLR7）激动剂相比，STING 激动剂诱导产生更广泛的促炎细胞因子谱。与 TLR7 激动剂不同，结构多样的 STING 激动剂通过诱导细胞凋亡部分耗尽 B 细胞和 NK 细胞，并完全耗尽 CD14+单核细胞。TANK 结合激酶 1 抑制剂可有效防止干扰素 α（IFNα）的分泌和细胞耗竭，表明其可能依赖于 cGAS-STING 途径的激活。最后，IFNα、肿瘤坏死因子-α、白细胞介素 6 和白细胞介素 1β的分泌以及 CD14+单核细胞的凋亡是对 STING 激动剂的主要反应，而 IFNγ 则是次级分泌。这些发现为 cGAS-STING 途径的免疫调节提供了新的见解，这对未来的治疗具有重要意义。
