A Role for Stimulator of Interferon Genes in Toll-Like Receptor 8 Signaling

Abstract The innate immune system is equipped with multiple receptors to detect microbial nucleic acids and induce type I interferon (IFN) restrict viral replication. When dysregulated these receptor pathways inflammation in response host promote development persistence of autoimmune diseases like Systemic Lupus Erythematosus (SLE). IFN production regulated by the Interferon Regulatory Factor (IRF) transcription factor family downstream several such as Toll-like (TLRs) Stimulator Genes (STING). Both TLRs STING activate TANK-binding kinase (TBKI) IkappaB kinase-ɛ (IKKɛ), which phosphorylate IRFs. pathway are considered independent. Here we show that plays a previously undescribed role human TLR8 signaling. Stimulation TL8-506 (TL8), ligand, induced secretion primary monocytes THP-1 cells was reduced inhibition STING. Using encoding reporters for IRF NFkB activity, two major signaling TLRs, found TL8 stimulation increased activity. inhibited, IRF, but not NFkB, activity reduced. TL8-induced dependent on IKKɛ, TBKI. Bulk RNA transcriptomic analysis induces gene signatures associated SLE downregulated These data demonstrate required full TLR8-IRF studies build new framework crosstalk between cytosolic endosomal receptors, could be used treat driven diseases.