Priming of Antiviral Innate Immune Responses in Specific Alveolar Macrophage Subsets by Cholesterol Deprivation

Cholesterol metabolism is associated with antiviral innate immune responses; however, its underlying mechanism is not fully elucidated. In this study, we performed a chemical screening to isolate small chemicals that affect the activities of the cytoplasmic viral RNA sensor RIG-I and found that statins, which inhibit cholesterol synthesis, markedly enhanced RIG-I-dependent type I interferon (IFN) production following viral infections. Restriction of cholesterol synthesis induced the expression of noncanonical type I IFNs, such as IFN-ω and IFN-α16, in the SREBP1 transcription factor-dependent manner. Produced noncanonical type I IFNs subsequently increased the expression of RIG-I via the type I IFN receptor, thereby augmenting RIG-I-dependent cytokine expression following viral infection. Administering statins augmented RIG-I-dependent cytokine expression in the mouse lung, and a mouse obesity model exhibited reduced RIG-I response in the lung compared to wild-type mice. Single-cell transcriptome analyses revealed a subset of alveolar macrophages that increase the RIG-I expression in response to the restriction of cholesterol synthesis in vivo. This study uncovered an alveolar macrophage population responding to cholesterol metabolism and priming antiviral innate immune responses. To investigate the impact of cholesterol metabolism in lung tissue, we injected Pitavastatin, which inhibits cholesterol biosynthesis, into mice and harvest their lung tissue. On the other hands, we also harvest lung tissue from Ob/Ob mice. And then, we constructed the sequence library for single cell-RNA seq.