Nishimura Tasuku, Kouwaki Takahisa, Takashima Ken, Ochi Akie, Mtali Yohana S, Oshiumi Hiroyuki
Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
School of Medicine, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
EMBO Rep. 2025 Jan;26(2):560-592. doi: 10.1038/s44319-024-00346-9. Epub 2024 Dec 12.
Cholesterol metabolism is associated with innate immune responses; however, the underlying mechanism remains unclear. Here, we perform chemical screening to isolate small molecules influencing RIG-I activity, a cytoplasmic viral RNA sensor. We find that statins, which inhibit cholesterol synthesis, dramatically enhance RIG-I-dependent antiviral responses in specific cell types. Since statins exhibit pleiotropic effects on type I interferon (IFN) responses, we further focus on their effects on RIG-I signaling. The restriction of cholesterol synthesis induces expression of noncanonical type I IFNs, such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This pathway subsequently enhances RIG-I-mediated signaling following viral infection. Administration of statins augments RIG-I-dependent cytokine expression in the lungs of mice. Conversely, a mouse obesity model shows a diminished RIG-I response. Single-cell transcriptome analyses reveal a subset of alveolar macrophages that increase RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study reveals SREBP1-mediated noncanonical type I IFN expression, linking cholesterol metabolism and RIG-I signaling.
胆固醇代谢与先天性免疫反应相关；然而，其潜在机制仍不清楚。在此，我们进行化学筛选以分离影响RIG-I活性的小分子，RIG-I是一种细胞质病毒RNA传感器。我们发现，抑制胆固醇合成的他汀类药物可显著增强特定细胞类型中RIG-I依赖性抗病毒反应。由于他汀类药物对I型干扰素（IFN）反应具有多效性，我们进一步关注它们对RIG-I信号传导的影响。胆固醇合成的限制以SREBP1转录因子依赖性方式诱导非经典I型IFN（如IFN-ω）的表达。该途径随后在病毒感染后增强RIG-I介导的信号传导。给予他汀类药物可增强小鼠肺中RIG-I依赖性细胞因子的表达。相反，小鼠肥胖模型显示RIG-I反应减弱。单细胞转录组分析揭示了一部分肺泡巨噬细胞，它们在体内对胆固醇合成受抑制的反应中增加RIG-I表达。本研究揭示了SREBP1介导的非经典I型IFN表达，将胆固醇代谢与RIG-I信号传导联系起来。
