Abstract
AbstractThe innate immune system is equipped with multiple receptors to detect microbial nucleic acids and induce type I interferon (IFN) to restrict viral replication. When dysregulated these receptor pathways induce inflammation in response to host nucleic acids and promote development and persistence of autoimmune diseases like Systemic Lupus Erythematosus (SLE). IFN production is regulated by the Interferon Regulatory Factor (IRF) transcription factor family of proteins that function downstream of several innate immune receptors such as Toll-like receptors (TLRs) and Stimulator of Interferon Genes (STING). Although both TLRs and STING activate the same downstream molecules, the pathway by which TLRs and STING activate IFN response are thought to be independent. Here we show that STING plays a previously undescribed role in human TLR8 signaling. Stimulation with the TLR8 ligands induced IFN secretion in primary human monocytes, and inhibition of STING reduced IFN secretion from primary monocytes from 8 healthy donors. We demonstrate that TLR8-induced IRF activity was reduced by STING inhibitors. Moreover, TLR8-induced IRF activity was blocked by inhibition or loss of IKKε, but not TBK1. Bulk RNA transcriptomic analysis supported a model where TLR8 induces transcriptional responses associated with SLE that can be downregulated by inhibition of STING. These data demonstrate that STING is required for full TLR8-to-IRF signaling and provide evidence for a new framework of crosstalk between cytosolic and endosomal innate immune receptors, which could be leveraged to treat IFN driven autoimmune diseases.BackgroundHigh levels of type I interferon (IFN) is characteristic of multiple autoimmune diseases, and while TLR8 is associated with autoimmune disease and IFN production, the mechanisms of TLR8-induced IFN production are not fully understood.ResultsSTING is phosphorylated following TLR8 signaling, which is selectively required for the IRF arm of TLR8 signaling and for TLR8-induced IFN production in primary human monocytes.ConclusionSTING plays a previously unappreciated role in TLR8-induced IFN productionSignificanceNucleic acid-sensing TLRs contribute to development and progression of autoimmune disease including interferonopathies, and we show a novel role for STING in TLR-induced IFN production that could be a therapeutic target.
Publisher
Cold Spring Harbor Laboratory