Type I Interferon promotes MxA-dependent IL-1b release in SLE monocytes

Systemic lupus erythematosus (SLE) is characterized by upregulation of Type Ι Interferon (IFN) and widespread inflammation. However, blocking the IFN pathway benefits a fraction of patients, pointing to additional pathogenic players. Here we describe monocytes (Mo) undergoing erythrophagocytosis and co-expressing IFN-inducible genes (ISGs) and interleukin-1b (IL-1b) in patients with active disease. This phenotype is recapitulated in vitro upon internalization of red blood cells carrying mitochondria (Mito+ RBCs), a feature of SLE. While ISG expression requires the interaction between Mito+ RBC-derived mitochondrial DNA (mtDNA) and cGAS, the production of IL-1b entails Mito+ RBC-derived mitochondrial RNA (mtRNA) triggering RIG-I-like receptor (RLR) activation. This leads to the cytosolic release of Mo-derived mtDNA and activation of the NLRP3 inflammasome. Importantly, the Type I IFN-inducible protein myxovirus resistant protein 1 (MxA) enables IL-1b release by routing this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. As Type I IFN and IL-1b are thought to counter-regulate each other, our study highlights an unprecedented synergy between these two cytokine pathways in SLE. Human Monocytes (Mo) or BLaER1 Mo were cocultured with CFSE labeled red blood cells carrying (Mito+) or not carrying (Mito-) RBCs in complete RPMI medium. 18 hr later Mo or BLaER1 Mo internalizing RBCs were FACS sorted and processesed for RNAseq analysis