Xu Lingxiao, Lyu Jiao, Qiu Zuocheng, Liu Qianghui, Hu Huan, Zhao Longwei, Pan Mingyu
Department of Rheumatology and Immunology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China; Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, China, Nanjing, China.
School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Int Immunopharmacol. 2025 Feb 6;147:114014. doi: 10.1016/j.intimp.2025.114014. Epub 2025 Jan 9.
Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling pathway, an essential element in the innate antiviral immune responses, has emerged as a key component of innate immune system to modulate type I IFNs production and response by recognizing both exogenous and endogenous DNA. Although some cGAS-STING signaling small molecule agonists have been developed, there are few natural polysaccharides reported to activate cGAS-STING signaling for the treatment of infectious diseases. Here, we reported that Laminaran, a low molecular weight β-glucan storage polysaccharide present in brown algae, potentiates cGAS-STING signaling to promote type I IFNs production and antiviral response. Laminaran enhanced cGAS-STING signaling mediated type I IFNs production and response both in human and murine cells upon HSV-1 infection or DNA mimics stimulation. Importantly, we found that Laminaran markedly inhibited Herpes simplex virus-1 (HSV-1) induced death and inflammatory responses and increased the induction of type I IFNs in C57BL/6J mice. Mechanistically, we found Laminaran inhibited autophagy and suppressed STING autophagic degradation to positively regulate cGAS-STING signaling response. Taken together, we uncovered the function of Laminaran in DNA triggered innate immunity by enhancing cGAS-STING signaling response. Laminaran might be a potential therapeutic candidate for viral infectious diseases.
环鸟苷酸-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）信号通路是天然抗病毒免疫反应的重要组成部分，已成为天然免疫系统的关键成分，通过识别外源性和内源性DNA来调节I型干扰素的产生和反应。尽管已经开发了一些cGAS-STING信号小分子激动剂，但据报道，很少有天然多糖能激活cGAS-STING信号来治疗传染病。在此，我们报道了海带多糖，一种存在于褐藻中的低分子量β-葡聚糖储存多糖，可增强cGAS-STING信号，促进I型干扰素的产生和抗病毒反应。在单纯疱疹病毒1型（HSV-1）感染或DNA模拟物刺激后，海带多糖在人和小鼠细胞中均增强了cGAS-STING信号介导的I型干扰素的产生和反应。重要的是，我们发现海带多糖显著抑制HSV-1诱导的死亡和炎症反应，并增加C57BL/6J小鼠中I型干扰素的诱导。机制上，我们发现海带多糖抑制自噬并抑制STING的自噬降解，从而正向调节cGAS-STING信号反应。综上所述，我们通过增强cGAS-STING信号反应揭示了海带多糖在DNA触发的天然免疫中的功能。海带多糖可能是病毒感染性疾病的潜在治疗候选物。
