Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Medical Sciences Program, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Sci Rep. 2024 May 14;14(1):11020. doi: 10.1038/s41598-024-61597-z.
The absence of stimulator of interferon genes (STING) in 129.B6.Fcgr2b-deficient mice rescue lupus phenotypes. The administration of a STING inhibitor (ISD017) into the young 129.B6.Fcgr2b-deficient mice prevents lupus nephritis development. This study mainly aimed to evaluate the effects of STING inhibition (ISD107) on established SLE in mice to prove that ISD017 could be a good therapeutic drug to reverse the already set-up autoimmunity and kidney impairment. Twenty-four-week-old Fcgr2b-deficient mice were treated with cyclophosphamide (25 mg/kg, intraperitoneal, once per week), ISD017 (10 mg/kg, intraperitoneal, three times per week), or control vehicle for 8 weeks, and were analyzed for phenotypes. Both ISD017 and cyclophosphamide treatment increased long-term survival and reduced the severity of glomerulonephritis in Fcgr2b-deficient mice. While cyclophosphamide reduced activated B cells (B220GL-7), ISD017 decreased activated T cells (CD4CD69) and neutrophils (Ly6cLy6g) in Fcgr2b-deficient mice. In addition, ISD017 reduced IL-1β and interferon-inducible genes. In summary, ISD017 treatment in symptomatic 129.B6.Fcgr2b-deficient mice reduced the severity of glomerulonephritis and increased long-term survival. ISD017 worked comparably to cyclophosphamide for treating lupus nephritis in 129.B6.Fcgr2b-deficient mice. ISD017 reduced activated T cells and neutrophils, while cyclophosphamide targeted activated B cells. These results suggested that STING inhibitors can potentially be a new therapeutic drug for treating lupus.
干扰素基因刺激物（STING）缺失可挽救 129.B6.Fcgr2b 缺陷小鼠的狼疮表型。在年轻的 129.B6.Fcgr2b 缺陷小鼠中给予 STING 抑制剂（ISD017）可预防狼疮肾炎的发生。本研究主要旨在评估 STING 抑制（ISD107）对已建立的 SLE 小鼠的影响，以证明 ISD017 可能是一种治疗药物，可逆转已建立的自身免疫和肾脏损伤。用环磷酰胺（25mg/kg，腹腔内，每周一次）、ISD017（10mg/kg，腹腔内，每周三次）或对照载体处理 24 周龄的 Fcgr2b 缺陷小鼠 8 周，并进行表型分析。ISD017 和环磷酰胺治疗均增加了 Fcgr2b 缺陷小鼠的长期存活率并降低了肾小球肾炎的严重程度。虽然环磷酰胺减少了活化的 B 细胞（B220GL-7），但 ISD017 减少了 Fcgr2b 缺陷小鼠中的活化 T 细胞（CD4CD69）和中性粒细胞（Ly6cLy6g）。此外，ISD017 减少了 IL-1β 和干扰素诱导基因。总之，在有症状的 129.B6.Fcgr2b 缺陷小鼠中，ISD017 治疗可降低肾小球肾炎的严重程度并增加长期存活率。ISD017 治疗对 129.B6.Fcgr2b 缺陷小鼠的狼疮肾炎与环磷酰胺作用相当。ISD017 减少活化的 T 细胞和中性粒细胞，而环磷酰胺靶向活化的 B 细胞。这些结果表明，STING 抑制剂可能成为治疗狼疮的一种新的治疗药物。
