In some individuals with systemic lupus erythematosus (SLE), red blood cells retain their mitochondria (Mito+ RBCs), and internalization of Mito+ RBCs by macrophages triggers the production of type I interferon. Findings now identify a subset of monocytes, which are expanded in active SLE, that internalize Mito+ RBCs and subsequently express interferon-stimulated genes, leading to IL-1β production via an unconventional secretory pathway.

The researchers found that the expression of type I interferon in this subset of monocytes was dependent on the sensing of both mitochondrial DNA (mtDNA, mediated by cGAS) and mitochondrial RNA (mtRNA, mediated by RIG-I receptors (RLRs)). The sensing of mtRNA from internalized Mito+ RBCs via the RLR antiviral signalling adaptor pathway also induced the production of IL-1β in these cells, by triggering the cytosolic release of monocyte mtDNA that activates the NLRP3 inflammasome.