Abstract
The recognition of cytosolic nucleic acids is a critical step in the host immune response against danger signals, such as molecular patterns from pathogens or tissue damage. Nonetheless, over-reactivity to self-nucleic acids leads to the sustained production of type I interferon (IFN), mediated either by cGAS or RLR, contributing to the pathogenesis of certain autoimmune diseases, such as Aicardi-Goutières syndrome (AGS). Therefore, inhibiting excessive IFN production represents a potential therapeutic strategy for such autoimmune conditions. In this study, we discovered that petroselinic acid (PA), a natural compound isolated from Apiaceae family plants, effectively suppresses type I IFN production induced by cytosolic nucleic acids. Mechanistic investigations revealed that PA inhibits the phosphorylation of TBK1 and IRF3, which are key nodal proteins within the type I interferon pathway. Notably, molecular docking suggests potential binding between PA and cytosolic nucleic acid sensors, such as cGAS and RIG-I. Moreover, we found that PA effectively attenuates the expression of type I IFN and their downstream interferon-stimulated genes (ISGs) in models of AGS autoimmune disease characterized by excessive nucleic acid accumulation. Thus, our research identifies a natural compound that offers a promising strategy for treating autoimmune diseases resulting from aberrant self-nucleic acid recognition and the hyperactivation of type I interferon.