Abstract
Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN (1) . Thus, defective removal of mitochondria from mature red blood cells (Mito (+) RBCs), a feature of SLE, contributes to IFN production by myeloid cells (2) . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1β (IL-1β) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito (+) RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1β production entails Mito (+) RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1β release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.