Cholesterol Restriction Primes RIG-I Antiviral Responses Through a Noncanonical Type I IFN Pathway

Cholesterol metabolism is associated with innate immune responses; however, the mechanisms underlying this have not been fully elucidated. Here, we performed a chemical screening to isolate small molecules affecting the activity of RIG-I, a cytoplasmic viral RNA sensor, and found that statins, which inhibit cholesterol synthesis, dramatically enhanced RIG-I-dependent antiviral responses in specific cell types. The restriction of cholesterol synthesis induced the expression of noncanonical type I interferons (IFNs), such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This noncanonical type I IFN expression pathway subsequently enhanced RIG-I-mediated signaling following viral infection. Administration of statins in mice augmented RIG-I-dependent cytokine expression in the lungs. Conversely, a mouse obesity model exhibited reduced RIG-I response in the lungs compared to wild-type mice. Single-cell transcriptome analyses revealed a subset of alveolar macrophages that increased the RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study revealed the noncanonical type I IFN pathway linking cholesterol metabolism and RIG-I signaling. Targeting this pathway could offer valuable insights for developing novel treatment approaches to address future viral pandemics.